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|Coordinate||122,582,439 bp (GRCm38)|
|Base Change||T ⇒ C (forward strand)|
|Gene Name||protein kinase C, beta|
|Synonym(s)||Pkcb, Prkcb2, Prkcb1, A130082F03Rik, PKC-Beta|
|Chromosomal Location||122,288,751-122,634,402 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role in cells. The protein encoded by this gene is one of the PKC family members. This protein kinase has been reported to be involved in many different cellular functions, such as B cell activation, apoptosis induction, endothelial cell proliferation, and intestinal sugar absorption. Studies in mice also suggest that this kinase may also regulate neuronal functions and correlate fear-induced conflict behavior after stress. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]
PHENOTYPE: Mice homozygous for a null allele exhibit impaired humoral immune responses, altered proliferative responses of B cells to various stimuli, abnormal vascular wound healing, and deficits in contextual and cued fear conditioning. ENU-induced mutations leadto impaired T cell-independent IgM responses. [provided by MGI curators]
|Amino Acid Change||Tyrosine changed to Histidine|
|Institutional Source||Beutler Lab|
Y417H in Ensembl: ENSMUSP00000070019 (fasta)
|Gene Model||not available|
|Predicted Effect||probably damaging
PolyPhen 2 Score 0.996 (Sensitivity: 0.54; Specificity: 0.98)
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Dominant|
|Local Stock||Live Mice, Sperm, gDNA|
|Last Updated||2018-09-18 3:54 PM by Diantha La Vine|
|Record Created||2009-05-08 12:00 AM|
Untied was identified in a forward genetic screen for mutations that impair the T cell-independent immunologic (Ig)M response to the model antigen 2,4,6-trinitrophenyl (TNP)-Ficoll (see the T-independent B Cell Response Screen). The index mouse, BB190, mounted a weak IgM response to NP-ficoll. To confirm the mutation, a group of 22 G3 siblings were immunized with TNP-ficoll, and on day seven, serum samples were collected. TNP-specific IgM was measured by ELISA. Of the 22 mice tested, five mice had high TNP-specific IgM responses, nine had intermediate responses, and seven had low TNP-specific IgM responses (circled in the figure below). These data suggest that the Untied phenotype is semidominant with heterozygous animals displaying intermediate responses to TNP-Ficoll relative to wild type controls and homozygous mice.
|Nature of Mutation|
The Untied mutation was mapped to Chromosome 7, and corresponds to a T to C transition at position 1469 of the Prkcb transcript, in exon 11 of 17 total exons.
The mutated nucleotide is indicated in red lettering, and results in a tyrosine to histidine substitution at amino acid 417 of the PKCβ protein.
Conventional PKCs interact weakly with membranes in the absence of Ca2+ or DAG. Agonists that promote phosphoinositide (PI) hydrolysis and inositol-1,4,5-trisphosphate (IP3) generation lead to the mobilization of intracellular Ca2+, which binds the C2 domain and increases the affinity of cPKCs for membranes. The initial interaction of PKC-C2 with membranes is low affinity. However, once anchored to membranes, cPKCs diffuse within the plane of the lipid bilayer and participate in a secondary C1A domain interaction with DAG, the membrane restricted product of PI hydrolysis. The coordinate C1/C2 domain binding to membrane components leads to a conformational change that releases the autoinhibitory pseudosubstrate domain from the substrate-binding pocket of the enzyme. In order for these allosteric interactions to occur, PKC must first be properly folded and in the correct conformation permissive for catalytic action. This is dependent upon the phosphorylation of Thr500 in the activation loop of the catalytic region. Subsequent autophosphorylation of Thr641 in the turn motif present in the C-terminal V5 domain maintains catalytic competence, and autophosphorylation on Ser660 in the V5 hydrophobic motif appears to release the kinase into the cytosol (2;3).
In PKCβ isoforms, the C1 domain occurs at residues 36-151 and can be subdivided into an A and B domain, each containing a characteristic DAG-binding motif, HX12CX2CXnCX2CX4HX2CX7C, where H is histidine, C is cysteine, X is any other amino acid, and n is 13 or 14 (2). Although the crystal structure of the PKCB C1 domain has not been determined, the structure of the closely related PKCα C1B domain complexed with a DAG-analogue has been solved (4). The upper third of the C1 domain forms a largely hydrophobic surface, while positively charged residues that interact with anionic phospholipids are exposed on the middle third of the C1 domain structure. The bottom third of the C1 domain contains the two Zn2+ coordinating sites, each formed by three cysteines and one histidine, that are required for proper domain folding. Initially, the C1 domain positively charged residues interact with electrostatically anionic membrane phospholipids. This interaction allows the C1 domain to penetrate the membrane bilayer and bind DAG, which is located more deeply within the membrane. DAG then binds to a narrow polar groove present in the otherwise highly conserved hydrophobic surface at the top of the domain formed by C1A residues Trp58/Phe60 and C1B residues Tyr123/Leu125. The C1 subdomains of PKCs do not always bind to DAG with the same affinity. For instance, the PKCα C1A domain has high affinity for DAG (likely true for PKCβ as well), while PKCα and PKCβ C1B DAG interactions are very weak (5). Other PKC enzymes bind DAG with high affinity through their C1B domains (6). The structural basis for these differences depends on the presence of a tryptophan or tyrosine in the lipid-binding surface of the C1B domain. C1B domains containing tryptophan at this position bind DAG with high affinity, while C1B domains containing tyrosine (Tyr123 in PKCβ) do not (5). The C1 domains of PKCα and PKCβ also show a strong preference for PS over other lipids (7;8). PS plays an important role to disrupt electrostatic interactions that form between C1 residues and residues found in the C2 domain, amino acids Asp55-Arg252 and Arg42-Glu282. These interactions maintain PKC enzymes in a closed conformation in the resting state, and disruption of this closed conformation allows the C1A domain to penetrate the membrane, bind to DAG, and trigger the conformational changes leading to enzyme activation (8).
The C2 domain is approximately 130 amino acids long and binds to anionic phospholipids present in membranes in a Ca2+-dependent manner. The structure of the PKCβ C2 domain is made up of eight anti-parallel β-strands connected by variable loops to form a Greek key β-sandwich fold (9) (Figure 4A). Three Ca2+ ions are coordinated by the highly conserved aspartic acid residues 187, 193, 246, 248, and 254 present in two opposing loops at one end of the domain, located at amino acids 186-195 and 245-256. Asn189 in this domain is important for the preferential binding of PKCα and PKCβ to PS over other membrane lipids, while Arg252 contributes to electrostatic interactions with the membrane. Trp245 and Trp247 are involved in hydrophobic interactions with the membrane, and the highly basic lysine-rich β3- and β4-sheets localize active enzyme to phosphatidylinositol 4,5-bisphosphate (PIP2)-enriched membranes (9-13). PKCβ also binds to the membrane-associated scaffolding protein receptor for activated protein kinase C 1 (RACK1) through three sites present in its C2 domain; MDPNGLSDPYVKLat amino acids 186-198, KGKTKTIK at residues 209-216, and SLNPEWNET at amino acids 218-226. These binding sites occur on β-strands in the domain, with the first binding site located on β-strand 3, adjacent and anti-parallel to a RACK-mimetic sequence known as the pseudo (ψ)-RACK site (SVEIWD at residues 241-246) on β6 with homology to RACK PKC binding sites. Molecular interactions between the RACK1-binding site and ψ-RACK stabilize the β-sandwich structure of the C2 domain (14). The binding of ψ-RACK to PKCβ RACK binding sites is of lower affinity than PKC binding to RACK proteins.
The catalytic domain of PKCβII at amino acids 339-673 has also been determined (15), and follows the classical bilobal fold present in kinases. The N-terminal lobe (residues 339-421) consists of a five-stranded β-sheet (β1-β5) and two α-helices (αB, αC). The C-terminal lobe (residues 426-620) contains eight α-helices, and is connected to the N-terminal region by a linker comprised of amino acids 422-425 (Figure 4B). Both the ATP- and substrate-binding sites are located in the cleft formed by these two lobes. This is also where the pseudosubstrate domain of the regulatory region binds. The ATP-binding site at amino acids 348-356 consists of a characteristic glycine-rich sequence. An invariant Lys at amino acid 371 forms an ion pair with Glu390 from helix αC, properly aligning helix αC for substrate binding and catalysis. A gatekeeper residue (Met420), usually conserved as a large hydrophobic amino acid, controls access to a preexisting cavity in the ATP binding pocket. The activation loop present in the C-terminal lobe emanates from the base of the catalytic site and contains the conserved Asp466, which interacts with the nucleophilic hydroxyl side chain of the substrate. This loop also contains Asn471, which serves to stabilize the orientiation of Asp466. Asn471 and Asp484 form part of the Asp-Phe-Gly (DFG) motif at the base of the activation loop that is required for the binding of two divalent cations (Mg2+) involved in nucleotide recognition (2;15). Both the activation loop and V5 domain contain highly conserved phosphorylation sites that are critical for structuring the catalytic pocket (2;15). The V5 domain wraps around the N-lobe and contains a novel α-helix near the proline-flanked turn motif at amino acids 637-643, which contains the autophosphorylation site Thr641 (15). The V5 domain also contains a conserved phosphorylation site flanked by hydrophobic residues (FXXFS/TF/Y at residues 656-661), known as the hydrophobic motif. The hydrophobic motif contains a conserved phenylalanine next to the phosphorylation site that appears to interact with a hydrophobic pocket on the back side of the kinase active site, and stabilizes the structure to allow high-affinity interactions with ATP and substrate (2). The phosphorylation site in the activation loop is regulated by 3-phosphoinositide-dependent protein kinase 1 (PDK1) subsequent to PDK1 docking at the hydrophobic motif (2;16), while dephosphorylation of Ser660 is regulated by the PH domain leucine-rich repeat protein phosphatases, PHLPP1 and 2, and leads to PKC degradation (17). The dephosphorylated PKCβII turn motif has been shown to bind to the heat shock protein HSP70, an interaction that protects PKCβII from degradation (18). PKC substrate-binding sites contain basic amino acids close to the Ser/Thr to be phosphorylated, and PKC substrate proteins may include mitogen activated protein (MAP) kinases, inhibitor of nuclear factor-κB (IκB), the vitamin D3 receptor VDR, Raf kinase, calpain, and the epidermal growth factor receptor (EGFR; see the record for Velvet).
Although PKC V5 domains contain the conserved turn and hydrophobic motifs, the sequences at the extreme C-terminus are highly variable and are likely to provide important determinants of specific PKC functions. The two PKCβ isoforms encoded by the Prkcb gene are translated from alternatively spliced products of the PKCβ pre-mRNA, and only differ from each other by a single C-terminal exon encoding the V5 variable region (19). Although RACK1 binding sites occur in the PKCβ C2 domain and are thus common to both isoforms, PKCβII appears to interact more specifically with RACK1 due to the presence of additional putative RACK1 binding motifs in its V5 domain; ACGRNAE at amino acids 621-627, QEVIRN at amino acids 645-650, and SFVNSEFLKPEVKS at amino acids 660-673. PKCβI also contains a RACK1 binding sequence in its V5 domain; KLFIMN at amino acids 645-650. Two non-conserved residues in the PKCβII domain (Asn625 and Lys668) are necessary for distinct subcellular translocation patterns associated with this isoform and are located in the RACK1 binding sites (20;21) (see Expression and Localization). The PKCβII V5 domain contains an actin binding site at amino acids 629-640, which also plays an important role in subcellular localization (22;23). PKCβI Tyr661 is phosphorylated by the tyrosine kinase Syk (spleen tyrosine kinase), which requires prior phosphorylation of the adjacent hydrophobic motif phosphorylation site. Once phosphorylated, this tyrosine residue binds to the Src-homology 2 (SH2)domain of the adaptor protein growth factor receptor-bound protein 2 (Grb2), leading to the activation of the Ras/extracellular regulated kinase (ERK) pathway (24). Potential NLS sequences are present in most PKC V5 domains, but this has only been tested in PKCδ, a novel PKC member (25).
The Untied mutation results in the substitution of a histidine for a tyrosine at amino acid 417 located in the kinase domain of the protein (Figure 3 and Figure 4B).
In their inactive conformations, most PKC proteins are localized in the cytosol and often associate with other proteins of the cytoskeleton (26). Upon activation, cPKCs have been shown to translocate to the plasma membrane via a mechanism that involves phospholipase C (PLC)-derived DAG accumulation (27;28). For instance, activation of B cells through B cell receptor (BCR) signaling leadsto translocation of PKCβ into specialized membranemicrodomains called lipid rafts (29). However, many PKC enzymes exhibit complex spatiotemporal expression patterns in cells. In cells that display a biphasic DAG response, PKCα and PKCβII, but not PKCβ1, are released from the plasma membrane and relocalize to a perinuclear site known as the pericentron, a subset of recycling endosomes containing the small GTPase Rab11 (30-32). In cardiomyocytes, endogenous PKCβ1 localizes to the cytosol and perinuclear region under basal conditions and translocates to the nucleus following treatment with phorbol 12-myristate 13-acetate (PMA), whereas PKCβII decorates fibrillar cytoskeletal structures at rest and translocates to the cell periphery and the perinuclear region, colocalizing with the PKC anchoring protein RACK1 (33;34). Interactions of PKC enzymes with RACK proteins are important for PKC subcellular localization as peptides containing the PKCβ1 and PKCβII–specific RACK1 binding sequences can act as isoform-specific translocation inhibitors during cell stimulation (20). In response to metabotropic glutamate receptor-1a (mGluR1a) activation, PKCβ1 and PKCβII oscillate differently between the cytosol and membrane. PKCα and PKCβI display three distinct patterns of activity: 1) agonist-independent oscillations, 2) agonist-stimulated oscillations, and 3) persistent plasma membrane localization in response to mGluR1a activation. In contrast, only agonist-stimulated PKCβII translocation responses are observed in mGluR1a-expressing cells (21;22). In a human erythroleukemia cell line, PKCβII selectively translocates to the nucleus during the G2/M stage of the cell cycle and directly phosphorylates the nuclear envelope protein lamin B at mitosis-specific sites involved in mitotic nuclear lamina disassembly (35;36). The 13 C-terminal amino acids of PKCβII are sufficient to confer PKCβII-like subcellular localization to PKCα in these cells (37). In addition, PKCβII accumulates in the cytoskeleton at actin-rich microfilaments in certain cell types due to the actin-binding site present in its V5 domain (22;23), and can localize to the centrosome by binding to the centrosomal protein pericentrin via its C1A domain (38). PKCβI has been shown to co-localize with microtubules and bind microtubule-associated proteins (39). Treatment of various cell types with insulin regulates PRKCB/Prkcb gene splicing to preferentially express the PKCβII isoform (40;41).
Generally, PKCβ isoforms are found in most tissues and cell types at some level. However, various studies suggest dynamic expression levels occur during embryonic development, and in some tissues in response to specific conditions. In rats, both isoforms are present in the greatest amount in the brain and spleen. PKCβ1 antisera stained peripheral cells within the islets of Langerhans of the pancreas most intensely, but was also found in the stratum granulosum of the cerebellum, and granulosa cells of the ovarian follicles, the spleen, heart, adrenal glands, and lung. Light staining was observed in the testes and no protein was seen in the liver or pituitary gland. A similar expression pattern was observed for PKCβII, except that PKCβII was more strongly expressed in Sertoli cells and cells of the spermatogenetic line in the testes (42). A detailed analysis of PKCβ isoforms in the rat brain found them to be widely expressed in neurons with PKCβ1 exhibiting various patterns of cytoplasm localization and PKCβII often found associated with the Golgi (43;44). PKCβ expression is increased in aging rat brains (45). The cerebellar expression pattern of PKCβ isoforms was observed in multiple species (46-48), and mRNA for both PKCβ isoforms have been reported in the cat visual system (49). PKCβ has also been observed in the rat kidney (50). During development of kidney glomerular mesangial cells (MCs), PKCβI expression was observed in neonatal and adult MCs, but PKCβII was expressed specifically in neonatal MCs during proliferation (51).
In fetal mice at embryonic day (E) 17, PKCβ1 was found in all tissues examined, while PKCβII was absent in the lung and the liver (52). All PKC proteins are expressed during preimplantation development (53). PKCβ is highly expressed by chrondocytes in developing mouse skeletal structures (54), while PKCβII is dynamically expressed during murine palate development (55). PKCβ has also been reported to be upregulated during adipocyte differentiation (56).
PKCβ is upregulated in diffuse large B cell lymphoma (57), while PKCβII, specifically, is highly expressed in chronic lymphocytic leukemia (CLL) (58). A dramatic increase in PKCβII protein was also observed in colon tumors relative to normal colonic epithelium, while PKCβI was dramatically reduced in colon tumors (59). Although normally present in the upper cell layers of the human epidermis, particularly in dendritic Langerhans cells, PKCβ expression is absent from psoriatic skin lesions except in recruited immune cells (60).
Many functions have been ascribed to PKC kinases due to their wide-spread expression and variety of substrates. PKCs are involved in receptor desensitization, modulating membrane structure events, regulating transcription, mediating immune responses, regulating cell growth, and in learning and memory. A high degree of redundancy or cross-talk amongst different PKC proteins can also occur, making the identification of isoform-specific roles difficult. The development of knockout mice for various PKC genes has enabled identification of the in vivo pathways and processes these proteins are involved in as opposed to their broad in vitro substrate specificity. A targeted knockout of the Prkcb gene in mice resulted in animals with reduced numbers of mature peripheral B cells, a loss of peritoneal B-1 B cells, reduced T cell-independent antibody responses, as well as reduced function of various other immune cell types. PKCβ-deficient mice also exhibit a variety of minor metabolic deficiencies (61-66). The roles of PKCβ isoforms in B cell signaling, immune cell function, diabetic complications, and cancer are detailed below.
PKCβ appears to play a more minor role in the function of other immune cell types. Although PKCβ is expressed in T cells, T cell signaling is intact in PKCβ-deficient mice (82). However, activated T cell locomotion is impaired (63). During inflammation, T cells enter the peripheral inflamed tissues and crawl along microvascular endothelial cells in order to encounter inflammatory signals. T cell recruitment is mediated by the integrin receptor lymphocyte function-associated antigen 1 (LFA-1), which binds to the counter-receptor intercellular cell-adhesion molecule 1 (ICAM-1) expressed by endothelium at inflammatory sites. The activation of LFA-1 is associated with translocation of PKCβ1 to the microtubule cytoskeleton (83), while the expression of PKCβ1 in a PKCβ-deficient and nonmotile T cell line promoted cell polarization and enhanced motility (63). Prkcb-/- animals display defects in mast cell degranulation and release of interleukin (IL)-6, which are key features of IgE stimulation through the high affinity FceR1 receptor and requires PKC activity (62). In addition, PKCβ overexpressing mast cells exhibited an increased level of IL-6 and IL-2 mRNA (84). Activation of the mitogen activated protein (MAP) kinase cascade culminating in TNFα secretion (see the record for panr1) appears to be dependent on PKCβ in these cells (24;85). Platelets deficient in PKCβ are unable to spread on a fibrinogen-coated surface, although they do not show any change in agonist-induced fibrinogen binding. These results suggest that PKCβ is not required for agonist-induced activation of the fibrinogen receptor αIIbβ3, but is necessary for subsequent signaling to the actin cytoskeleton, which is required for cytoskeletal rearrangements necessary for full platelet aggregation. This activity requires the adaptor protein RACK1 (64). Finally, PKCβII activation appears to be required for dendritic cell (DC) differentiation, at least in vitro (86).
Members of the PKC family play important roles in signaling for various growth factors, cytokines, and hormones including those involved in the regulation of cell growth, apoptosis, and differentiation of hematopoietic cells. These include platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), erythropoietin (EPO), thrombopoietin (TPO), stem cell factor (SCF), tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, M-CSF, type I and II interferons (IFNs) and various interleukins (ILs). It is likely that multiple PKC enzymes play roles in the signaling from each of these factors, but the study of PKCβ activity specifically has only been implicated in TPO, IL-3, TNF, and GM-CSF [reviewed by (1)]. TPO is a glycoprotein hormone produced mainly by the liver and kidneys that functions as the major regulator of megakaryocytic precursor differentiation and proliferation in the bone marrow. TPO treatment of certain cell lines results in PKC enzyme activation including PKCα and PKCβ, and relocalization of both of these proteins to the membrane (87). Although PKCβ is not specifically implicated in SCF signaling, it is likely involved. SCF is a glycoprotein that serves as a ligand for the tyrosine kinase receptor c-kit (see the record for Pretty2 and Casper), and is an essential regulator of early hematopoiesis. PKC enzymes can directly phosphorylate c-kit on serine residues following SCF ligand binding, resulting in a decrease in receptor tyrosine autophosphorylation (88). Inhibition of PKC activity reversed this decrease in autophosphorylation. IL-3 is a cytokine with significant effects on cell proliferation and differentiation in various hematopoietic cell types, and PKCβ isoforms have been shown to be the predominant nuclear isoforms in certain IL-3 dependent hematopoietic cell lines (89;90). However, PKCβ is not required for IL-3/IL-4 induced mast cell proliferation (62).
Many receptor protein tyrosine kinases, such as EGFR, platelet-derived growth factor receptor (PDGFR) and the insulin receptor (IR), activate PLC and production of DAG, which in turn activates PKC enzymes (91). Downstream of the insulin receptor, PKCs may activate the Raf/MEK/ERK cascade. In response to insulin, activation of several PKC enzymes, including PKCβ, in skeletal muscle cells is dependent on the phosphorylation of the insulin receptor substrate 1 (IRS-1). Blocking PKCβ specifically decreased the insulin-induced ERK activity and subsequent DNA synthesis, without affecting EGF-stimulated mitogenesis, and also inhibited insulin-induced Raf activation (92). PKCβ activation may also provide an inhibitory feedback mechanism to down regulate insulin receptor autophosphorylation and activity (93), but this inhibition does not occur in all cell types (94). Glucose transport is increased in some tissues in PKCβ knockout mice, which may be partly due to the loss of PKCβ1 as PKCβ1 was specifically shown to negatively modulate insulin-stimulated translocation of the glucose transporter, GLUT4, to the plasma membrane (66). Interestingly, overexpression of PKCβII in NIH-3T3 cells enhanced the effects of insulin on glucose transport (40). These results, along with the insulin-stimulated regulation of PRKCB gene splicing, suggests that PKCB isoforms may have opposing effects on glucose transport in cells. However, other PKC enzymes have been shown to play important roles in mediating the metabolic effects of insulin, and it is not clear whether PKCβ isoforms play a significant role in this process (95).
PKCβ is also implicated in the pathogenesis of diabetes. Hyperglycemia activates PKC enzymes involved in the regulation of vascular permeability and contractility, endothelial cell activation and vasoconstriction, extracellular matrix (ECM) synthesis and turnover, abnormal angiogenesis, excessive apoptosis, leukocyte adhesion, abnormal growth factor signaling and cytokine action, as well as abnormal cell growth [reviewed by (96)]. In diabetic rats, PKCβII was shown to be preferentially increased in membrane fractions in the aorta, heart, and renal glomeration (97), while high glucose induced PKCβ1 activity in mesangial cell cultures (98). PRKCB gene synthesis is specifically increased in human diabetic kidneys (99). Specific inhibition of PKCβ ameliorated diabetic symptoms in diabetic animal models (100-102). When diabetes is induced in Prkcb-/- mice, complications due to hyperglycemia are reduced relative to wild type controls (103-105), and angiogenic response to oxygen-induced retinal ischemia was dramatically increased in transgenic mice overexpressing PKCβII (103).
PKCs have long been known to play important roles in the development of cancer. Phorbol esters are known to promote tumor formation and partially do so by activating PKC enzymes, thus promoting cellular survival and proliferation [reviewed by (106)]. PKCs were originally thought to be pro-mitogenic kinases, but this activity can be PKC-isozyme-dependent and cell-type dependent, as many PKCs can also inhibit cell cycle progression and promote apoptosis. Altered PKC levels are found in many types of human cancers. As mentioned above, PKCβII is overexpressed in CLL, a malignant disorder of mature B cells that is characterized by monoclonal expansion in blood, bone marrow, and lymphoid organs of cells arrested in the G0/G1 stage of the cell cycle. BCR signaling through PKCβII plays a role in the survival and expansion of these cells (58;107). PKCβII may also be an important mediator of vascular endothelial growth factor (VEGF)-induced angiogenesis and have a role in VEGF-induced endothelial cell proliferation, thus promoting the tumor vascular network. PKCβII is progressively induced in chemically induced colon carcinogenesis in mice, along with a concomitant reduction in PKCa and PKCβ1 (59). Furthermore, PKCβII transgenic mice display hyperproliferation of the colonic epithelium and are highly sensitive to carcinogen-induced colon cancer (108). In these cancerous cells, PKCβII activates the Ras/MEK pathway (109). In another type of cancer, PKC βII has been shown to be critical for nuclear lamina disassembly at the G2/M transition through phosphorylation of lamin B in K562 erythroleukemia cells (36). The relocalization of activated PKCβII from the plasma membrane to the pericentron (see Expression and Localization) has been implicated in the oncogenic transformation of cells, pathogenesis associated with hyperglycemia, and in cardiac hypertrophy (2). Localization to the pericentron is a consequence of sustained DAG formation through a PLC-independent mechanism involving phospholipase D (PLD), a membrane-bound enzyme that generates phosphatidic acid (PA), which is subsequently converted to DAG by PA phosphohydrolase (110;111). PKCβII at the pericentron may control hormone responses by regulating the trafficking of continuously recycling membrane signaling proteins and cell surface receptors. The lipid, ceramide, is able to inhibit this localization by stimulating a ceramide-activated protein phosphatase that reverses PKCβII activation loop phosphorylation (112;113). PKCβ-selective inhibitors have been shown to kill or suppress the proliferation of multiple types of cancer cells (114;115).
B cell responses are classified as T-dependent (T-D) or T-independent (T-I) based on their requirement for T cell help in antibody production. T cell-dependent antigens are processed and presented to helper T cells via the MHC class II molecules, whereas T cell-independent antigens are typically polysaccharides that cannot be processed and presented by MHC molecules. These antigens are often expressed on the surface of pathogens in an organized, highly repetitive form that can activate specific B cells by cross-linking of antigen receptors. The formation of antigen receptor clusters can recruit and activate multiple Btk molecules, resulting in long-term mobilization of intracellular ionized Ca2+, gene transcription and B cell activation and proliferation. Toll-like receptor (TLR) engagement provides a second signal that allows the secretion of antibody in response to these antigens. The T-D B cell response is mediated by conventional (follicular B-2) B cells, while T-I B cell responses are mediated by peritoneal B-1 and marginal zone (MZ) B cells [reviewed by (116;117)].
The reduction of B cell antibody responses to TNP-Ficoll in Untied mice suggests that the function of B-1 and/or MZ B cells is impaired in these animals with BCR signaling likely affected. These phenotypes are consistent with the phenotypes observed in Prkcb-/-animals, which also exhibit reduced T cell-independent antibody responses along with severe impairment of B-1 cells (61). B cell numbers have not been analyzed in Untied mice and it is unknown if the Untied allele is hypomorphic rather than functionally null. Mice heterozygous for the knockout allele have normal B cell numbers and B cell responses (29;61), which varies from the semidominant intermediate phenotype observed in Untied animals. The semidominant phenotype observed in Untied mice may be due to the expression of nonfunctional, but appropriately localized, PKCβ proteins that are then able to inhibit the appropriate localization and function of wild type kinases.
The amino acid substitution in Untied mice occurs close to the gatekeeper residue located in the kinase domain of PKCβ. The substitution of a histidine for a tyrosine may affect the overall structure and catalytic activity of the kinase domain, or it may affect the role of the gatekeeper residue on restricting access to the ATP binding pocket of the enzyme.
|Primers||Primers cannot be located by automatic search.|
Untied genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide transition.
Untied(F): 5’- TGTTCCAGCAAACCCTGAACTAGGT -3’
Untied(R): 5’- TCTCCCCAAGAGTCAGAGGGAAGA -3’
1) 95°C 2:00
2) 95°C 0:30
3) 56°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 29X
6) 72°C 7:00
7) 4°C ∞
Primers for sequencing
Untied_seq(F): 5'- AAAAGTGTTCTCATTCTACCTGTGC -3'
Untied_seq(R): 5’- TTAGCTGGCCTTCAGGAAC -3’
The following sequence of 953 nucleotides (NCBI Mouse Genome Build 37.1, Chromosome 7, bases 129,725,637 to 129,726,591) is amplified:
tgttccagca aaccctgaac taggtaataa tatcaattaa gtagtaagat ccatgtgtta
attatatttt ccagcacaaa tgaatttcaa tttgtagtta ttaattaaaa gtgttctcat
tctacctgtg ctagcctgca tgcttacagt ggctcagagg tcacccttag tgggtgctgg
gccctgcctg aaagaacact ccggagttct ggtagctctc atcataagtc ccagctactc
cctgctcccc gtttgggtcc tgagaaagta tggggtgctg actttggtgt ttgctctctt
tcctcaggac cgcctgtact ttgtgatgga gtatgtgaac gggggtgacc tcatgtacca
catccaacaa gttggccgtt tcaaggagcc ccatgctgtg taagacagac cctctttgtg
ccctttcctt gggataaatg attgtcattt cctttaagtt ttagcctact agggattttt
tttaccccaa catcccaggc ttcttctttg tgagcgttat ttggccaagg acaactgtat
tctgctcgct ttgagatgtt tctttatgtt cctgaaggcc agctaagaac tcatagctct
agaccaatga ctgtttcata atctctaatt tttttttgcc cctccatcct gagaaaggtc
ttataacttc cttggggaat gtctttgcag gttttttgtc tgttcatttg ctaatattta
ttgagagcgt tctttgtgcc agaccctcga gtactgaaca aacaccatct catttcatcc
tgagcggtac ggtgagggag agaatctcac ccaagcttta caatcaaggg caacgagacc
cggagggtgg gaaccgccaa gattctagac ctaggggagg gtctgtgtgg gtgagaccca
cctgtgtttg ttcatctgtt tcctacacct cttccctctg actcttgggg aga
Primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated T is indicated in red.
1. Redig, A. J., and Platanias, L. C. (2007) The Protein Kinase C (PKC) Family of Proteins in Cytokine Signaling in Hematopoiesis. J. Interferon Cytokine Res. 27, 623-636.
2. Steinberg, S. F. (2008) Structural Basis of Protein Kinase C Isoform Function. Physiol. Rev. 88, 1341-1378.
3. Keranen, L. M., Dutil, E. M., and Newton, A. C. (1995) Protein Kinase C is Regulated in Vivo by Three Functionally Distinct Phosphorylations. Curr. Biol. 5, 1394-1403.
4. Hommel, U., Zurini, M., and Luyten, M. (1994) Solution Structure of a Cysteine Rich Domain of Rat Protein Kinase C. Nat. Struct. Biol. 1, 383-387.
5. Dries, D. R., Gallegos, L. L., and Newton, A. C. (2007) A Single Residue in the C1 Domain Sensitizes Novel Protein Kinase C Isoforms to Cellular Diacylglycerol Production. J. Biol. Chem. 282, 826-830.
6. Melowic, H. R., Stahelin, R. V., Blatner, N. R., Tian, W., Hayashi, K., Altman, A., and Cho, W. (2007) Mechanism of Diacylglycerol-Induced Membrane Targeting and Activation of Protein Kinase Ctheta. J. Biol. Chem. 282, 21467-21476.
7. Slater, S. J., Seiz, J. L., Cook, A. C., Buzas, C. J., Malinowski, S. A., Kershner, J. L., Stagliano, B. A., and Stubbs, C. D. (2002) Regulation of PKC Alpha Activity by C1-C2 Domain Interactions. J. Biol. Chem. 277, 15277-15285.
8. Stahelin, R. V., Digman, M. A., Medkova, M., Ananthanarayanan, B., Melowic, H. R., Rafter, J. D., and Cho, W. (2005) Diacylglycerol-Induced Membrane Targeting and Activation of Protein Kinase Cepsilon: Mechanistic Differences between Protein Kinases Cdelta and Cepsilon. J. Biol. Chem. 280, 19784-19793.
9. Sutton, R. B., and Sprang, S. R. (1998) Structure of the Protein Kinase Cbeta Phospholipid-Binding C2 Domain Complexed with Ca2+. Structure. 6, 1395-1405.
10. Edwards, A. S., and Newton, A. C. (1997) Regulation of Protein Kinase C betaII by its C2 Domain. Biochemistry. 36, 15615-15623.
11. Medkova, M., and Cho, W. (1998) Mutagenesis of the C2 Domain of Protein Kinase C-Alpha. Differential Roles of Ca2+ Ligands and Membrane Binding Residues. J. Biol. Chem. 273, 17544-17552.
12. Corbalan-Garcia, S., Garcia-Garcia, J., Rodriguez-Alfaro, J. A., and Gomez-Fernandez, J. C. (2003) A New Phosphatidylinositol 4,5-Bisphosphate-Binding Site Located in the C2 Domain of Protein Kinase Calpha. J. Biol. Chem. 278, 4972-4980.
13. Stahelin, R. V., Rafter, J. D., Das, S., and Cho, W. (2003) The Molecular Basis of Differential Subcellular Localization of C2 Domains of Protein Kinase C-Alpha and Group IVa Cytosolic Phospholipase A2. J. Biol. Chem. 278, 12452-12460.
14. Banci, L., Cavallaro, G., Kheifets, V., and Mochly-Rosen, D. (2002) Molecular Dynamics Characterization of the C2 Domain of Protein Kinase Cbeta. J. Biol. Chem. 277, 12988-12997.
15. Grodsky, N., Li, Y., Bouzida, D., Love, R., Jensen, J., Nodes, B., Nonomiya, J., and Grant, S. (2006) Structure of the Catalytic Domain of Human Protein Kinase C Beta II Complexed with a Bisindolylmaleimide Inhibitor. Biochemistry. 45, 13970-13981.
16. Balendran, A., Hare, G. R., Kieloch, A., Williams, M. R., and Alessi, D. R. (2000) Further Evidence that 3-Phosphoinositide-Dependent Protein Kinase-1 (PDK1) is Required for the Stability and Phosphorylation of Protein Kinase C (PKC) Isoforms. FEBS Lett. 484, 217-223.
17. Gao, T., Brognard, J., and Newton, A. C. (2008) The Phosphatase PHLPP Controls the Cellular Levels of Protein Kinase C. J. Biol. Chem. 283, 6300-6311.
18. Gao, T., and Newton, A. C. (2002) The Turn Motif is a Phosphorylation Switch that Regulates the Binding of Hsp70 to Protein Kinase C. J. Biol. Chem. 277, 31585-31592.
19. Ono, Y., Kikkawa, U., Ogita, K., Fujii, T., Kurokawa, T., Asaoka, Y., Sekiguchi, K., Ase, K., Igarashi, K., and Nishizuka, Y. (1987) Expression and Properties of Two Types of Protein Kinase C: Alternative Splicing from a Single Gene. Science. 236, 1116-1120.
20. Stebbins, E. G., and Mochly-Rosen, D. (2001) Binding Specificity for RACK1 Resides in the V5 Region of Beta II Protein Kinase C. J. Biol. Chem. 276, 29644-29650.
21. Babwah, A. V., Dale, L. B., and Ferguson, S. S. (2003) Protein Kinase C Isoform-Specific Differences in the Spatial-Temporal Regulation and Decoding of Metabotropic Glutamate receptor1a-Stimulated Second Messenger Responses. J. Biol. Chem. 278, 5419-5426.
22. Goodnight, J. A., Mischak, H., Kolch, W., and Mushinski, J. F. (1995) Immunocytochemical Localization of Eight Protein Kinase C Isozymes Overexpressed in NIH 3T3 Fibroblasts. Isoform-Specific Association with Microfilaments, Golgi, Endoplasmic Reticulum, and Nuclear and Cell Membranes. J. Biol. Chem. 270, 9991-10001.
23. Blobe, G. C., Stribling, D. S., Fabbro, D., Stabel, S., and Hannun, Y. A. (1996) Protein Kinase C Beta II Specifically Binds to and is Activated by F-Actin. J. Biol. Chem. 271, 15823-15830.
24. Kawakami, Y., Kitaura, J., Yao, L., McHenry, R. W., Kawakami, Y., Newton, A. C., Kang, S., Kato, R. M., Leitges, M., Rawlings, D. J., and Kawakami, T. (2003) A Ras Activation Pathway Dependent on Syk Phosphorylation of Protein Kinase C. Proc. Natl. Acad. Sci. U. S. A. 100, 9470-9475.
25. DeVries, T. A., Neville, M. C., and Reyland, M. E. (2002) Nuclear Import of PKCdelta is Required for Apoptosis: Identification of a Novel Nuclear Import Sequence. EMBO J. 21, 6050-6060.
26. Keenan, C., and Kelleher, D. (1998) Protein Kinase C and the Cytoskeleton. Cell. Signal. 10, 225-232.
27. Newton, A. C. (2001) Protein Kinase C: Structural and Spatial Regulation by Phosphorylation, Cofactors, and Macromolecular Interactions. Chem. Rev. 101, 2353-2364.
28. Collazos, A., Diouf, B., Guerineau, N. C., Quittau-Prevostel, C., Peter, M., Coudane, F., Hollande, F., and Joubert, D. (2006) A Spatiotemporally Coordinated Cascade of Protein Kinase C Activation Controls Isoform-Selective Translocation. Mol. Cell. Biol. 26, 2247-2261.
29. Su, T. T., Guo, B., Kawakami, Y., Sommer, K., Chae, K., Humphries, L. A., Kato, R. M., Kang, S., Patrone, L., Wall, R., Teitell, M., Leitges, M., Kawakami, T., and Rawlings, D. J. (2002) PKC-Beta Controls I Kappa B Kinase Lipid Raft Recruitment and Activation in Response to BCR Signaling. Nat. Immunol. 3, 780-786.
30. Feng, X., Becker, K. P., Stribling, S. D., Peters, K. G., and Hannun, Y. A. (2000) Regulation of Receptor-Mediated Protein Kinase C Membrane Trafficking by Autophosphorylation. J. Biol. Chem. 275, 17024-17034.
31. Becker, K. P., and Hannun, Y. A. (2003) CPKC-Dependent Sequestration of Membrane-Recycling Components in a Subset of Recycling Endosomes. J. Biol. Chem. 278, 52747-52754.
32. Idkowiak-Baldys, J., Becker, K. P., Kitatani, K., and Hannun, Y. A. (2006) Dynamic Sequestration of the Recycling Compartment by Classical Protein Kinase C. J. Biol. Chem. 281, 22321-22331.
33. Disatnik, M. H., Buraggi, G., and Mochly-Rosen, D. (1994) Localization of Protein Kinase C Isozymes in Cardiac Myocytes. Exp. Cell Res. 210, 287-297.
34. Ron, D., Luo, J., and Mochly-Rosen, D. (1995) C2 Region-Derived Peptides Inhibit Translocation and Function of Beta Protein Kinase C in Vivo. J. Biol. Chem. 270, 24180-24187.
35. Goss, V. L., Hocevar, B. A., Thompson, L. J., Stratton, C. A., Burns, D. J., and Fields, A. P. (1994) Identification of Nuclear Beta II Protein Kinase C as a Mitotic Lamin Kinase. J. Biol. Chem. 269, 19074-19080.
36. Thompson, L. J., and Fields, A. P. (1996) BetaII Protein Kinase C is Required for the G2/M Phase Transition of Cell Cycle. J. Biol. Chem. 271, 15045-15053.
37. Gokmen-Polar, Y., and Fields, A. P. (1998) Mapping of a Molecular Determinant for Protein Kinase C betaII Isozyme Function. J. Biol. Chem. 273, 20261-20266.
38. Chen, D., Purohit, A., Halilovic, E., Doxsey, S. J., and Newton, A. C. (2004) Centrosomal Anchoring of Protein Kinase C betaII by Pericentrin Controls Microtubule Organization, Spindle Function, and Cytokinesis. J. Biol. Chem. 279, 4829-4839.
39. Kiley, S. C., and Parker, P. J. (1995) Differential Localization of Protein Kinase C Isozymes in U937 Cells: Evidence for Distinct Isozyme Functions during Monocyte Differentiation. J. Cell. Sci. 108 ( Pt 3), 1003-1016.
40. Chalfant, C. E., Mischak, H., Watson, J. E., Winkler, B. C., Goodnight, J., Farese, R. V., and Cooper, D. R. (1995) Regulation of Alternative Splicing of Protein Kinase C Beta by Insulin. J. Biol. Chem. 270, 13326-13332.
41. Patel, N. A., Apostolatos, H. S., Mebert, K., Chalfant, C. E., Watson, J. E., Pillay, T. S., Sparks, J., and Cooper, D. R. (2004) Insulin Regulates Protein Kinase CbetaII Alternative Splicing in Multiple Target Tissues: Development of a Hormonally Responsive Heterologous Minigene. Mol. Endocrinol. 18, 899-911.
42. Wetsel, W. C., Khan, W. A., Merchenthaler, I., Rivera, H., Halpern, A. E., Phung, H. M., Negro-Vilar, A., and Hannun, Y. A. (1992) Tissue and Cellular Distribution of the Extended Family of Protein Kinase C Isoenzymes. J. Cell Biol. 117, 121-133.
43. Hosoda, K., Saito, N., Kose, A., Ito, A., Tsujino, T., Ogita, K., Kikkawa, U., Ono, Y., Igarashi, K., and Nishizuka, Y. (1989) Immunocytochemical Localization of the Beta I Subspecies of Protein Kinase C in Rat Brain. Proc. Natl. Acad. Sci. U. S. A. 86, 1393-1397.
44. Saito, N., Kose, A., Ito, A., Hosoda, K., Mori, M., Hirata, M., Ogita, K., Kikkawa, U., Ono, Y., and Igarashi, K. (1989) Immunocytochemical Localization of Beta II Subspecies of Protein Kinase C in Rat Brain. Proc. Natl. Acad. Sci. U. S. A. 86, 3409-3413.
45. Goldberg, M., and Steinberg, S. F. (1996) Tissue-Specific Developmental Regulation of Protein Kinase C Isoforms. Biochem. Pharmacol. 51, 1089-1093.
46. Ase, K., Saito, N., Shearman, M. S., Kikkawa, U., Ono, Y., Igarashi, K., Tanaka, C., and Nishizuka, Y. (1988) Distinct Cellular Expression of Beta I- and Beta II-Subspecies of Protein Kinase C in Rat Cerebellum. J. Neurosci. 8, 3850-3856.
47. Hidaka, H., Tanaka, T., Onoda, K., Hagiwara, M., Watanabe, M., Ohta, H., Ito, Y., Tsurudome, M., and Yoshida, T. (1988) Cell Type-Specific Expression of Protein Kinase C Isozymes in the Rabbit Cerebellum. J. Biol. Chem. 263, 4523-4526.
48. Ashique, A. M., Kharazia, V., Yaka, R., Phamluong, K., Peterson, A. S., and Ron, D. (2006) Localization of the Scaffolding Protein RACK1 in the Developing and Adult Mouse Brain. Brain Res. 1069, 31-38.
49. Arckens, L., Zhang, F., Vanduffel, W., Mailleux, P., Vanderhaeghen, J. J., Orban, G. A., and Vandesande, F. (1995) Localization of the Two Protein Kinase C Beta-mRNA Subtypes in Cat Visual System. J. Chem. Neuroanat. 8, 117-124.
50. Kosaka, Y. (1988) Multiplicity and Tissue-Specific Expression of Protein Kinase C in Rat Tissues. Kobe J. Med. Sci. 34, 271-284.
51. Saxena, R., Saksa, B. A., Hawkins, K. S., and Ganz, M. B. (1994) Protein Kinase C Beta I and Beta II are Differentially Expressed in the Developing Glomerulus. FASEB J. 8, 646-653.
52. Bareggi, R., Grill, V., Zweyer, M., Narducci, P., and Martelli, A. M. (1995) Distribution of the Extended Family of Protein Kinase C Isoenzymes in Fetal Organs of Mice: An Immunohistochemical Study. Cell Tissue Res. 280, 617-625.
53. Dehghani, H., and Hahnel, A. C. (2005) Expression Profile of Protein Kinase C Isozymes in Preimplantation Mouse Development. Reproduction. 130, 441-451.
54. Bareggi, R., Neri, L. M., Grill, V., Cocco, L., and Martelli, A. M. (1994) An Immunohistochemical Study of Protein Kinase C Distribution in Fetal Mouse Vertebral Column. Anat. Embryol. (Berl). 190, 47-54.
55. Balasubramanian, G., Amann, J. F., and Reddy, C. S. (2000) Expression and Activity of Protein Kinase C Isoenzymes during Normal and Abnormal Murine Palate Development. J. Craniofac. Genet. Dev. Biol. 20, 26-34.
56. Guo, X., and Liao, K. (2000) Analysis of Gene Expression Profile during 3T3-L1 Preadipocyte Differentiation. Gene. 251, 45-53.
57. Hans, C. P., Weisenburger, D. D., Greiner, T. C., Chan, W. C., Aoun, P., Cochran, G. T., Pan, Z., Smith, L. M., Lynch, J. C., Bociek, R. G., Bierman, P. J., Vose, J. M., and Armitage, J. O. (2005) Expression of PKC-Beta Or Cyclin D2 Predicts for Inferior Survival in Diffuse Large B-Cell Lymphoma. Mod. Pathol. 18, 1377-1384.
58. Abrams, S. T., Lakum, T., Lin, K., Jones, G. M., Treweeke, A. T., Farahani, M., Hughes, M., Zuzel, M., and Slupsky, J. R. (2007) B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells is Regulated by Overexpressed Active Protein Kinase CbetaII. Blood. 109, 1193-1201.
59. Gokmen-Polar, Y., Murray, N. R., Velasco, M. A., Gatalica, Z., and Fields, A. P. (2001) Elevated Protein Kinase C betaII is an Early Promotive Event in Colon Carcinogenesis. Cancer Res. 61, 1375-1381.
60. Fisher, G. J., Tavakkol, A., Leach, K., Burns, D., Basta, P., Loomis, C., Griffiths, C. E., Cooper, K. D., Reynolds, N. J., and Elder, J. T. (1993) Differential Expression of Protein Kinase C Isoenzymes in Normal and Psoriatic Adult Human Skin: Reduced Expression of Protein Kinase C-Beta II in Psoriasis. J. Invest. Dermatol. 101, 553-559.
61. Leitges, M., Schmedt, C., Guinamard, R., Davoust, J., Schaal, S., Stabel, S., and Tarakhovsky, A. (1996) Immunodeficiency in Protein Kinase Cbeta-Deficient Mice. Science. 273, 788-791.
62. Nechushtan, H., Leitges, M., Cohen, C., Kay, G., and Razin, E. (2000) Inhibition of Degranulation and Interleukin-6 Production in Mast Cells Derived from Mice Deficient in Protein Kinase Cbeta. Blood. 95, 1752-1757.
63. Volkov, Y., Long, A., McGrath, S., Ni Eidhin, D., and Kelleher, D. (2001) Crucial Importance of PKC-Beta(I) in LFA-1-Mediated Locomotion of Activated T Cells. Nat. Immunol. 2, 508-514.
64. Buensuceso, C. S., Obergfell, A., Soriani, A., Eto, K., Kiosses, W. B., Arias-Salgado, E. G., Kawakami, T., and Shattil, S. J. (2005) Regulation of Outside-in Signaling in Platelets by Integrin-Associated Protein Kinase C Beta. J. Biol. Chem. 280, 644-653.
65. Yao, L. J., Leitges, M., and Vallon, V. (2006) Mice Lacking Protein Kinase C Beta Present Modest Increases in Systolic Blood Pressure and NH4Cl-Induced Metabolic Acidosis. Kidney Blood Press. Res. 29, 36-42.
66. Standaert, M. L., Bandyopadhyay, G., Galloway, L., Soto, J., Ono, Y., Kikkawa, U., Farese, R. V., and Leitges, M. (1999) Effects of Knockout of the Protein Kinase C Beta Gene on Glucose Transport and Glucose Homeostasis. Endocrinology. 140, 4470-4477.
67. Guo, B., Su, T. T., and Rawlings, D. J. (2004) Protein Kinase C Family Functions in B-Cell Activation. Curr. Opin. Immunol. 16, 367-373.
68. Saijo, K., Mecklenbrauker, I., Santana, A., Leitger, M., Schmedt, C., and Tarakhovsky, A. (2002) Protein Kinase C Beta Controls Nuclear Factor kappaB Activation in B Cells through Selective Regulation of the IkappaB Kinase Alpha. J. Exp. Med. 195, 1647-1652.
69. Petro, J. B., Rahman, S. M., Ballard, D. W., and Khan, W. N. (2000) Bruton's Tyrosine Kinase is Required for Activation of IkappaB Kinase and Nuclear Factor kappaB in Response to B Cell Receptor Engagement. J. Exp. Med. 191, 1745-1754.
70. Bajpai, U. D., Zhang, K., Teutsch, M., Sen, R., and Wortis, H. H. (2000) Bruton's Tyrosine Kinase Links the B Cell Receptor to Nuclear Factor kappaB Activation. J. Exp. Med. 191, 1735-1744.
71. Kang, S. W., Wahl, M. I., Chu, J., Kitaura, J., Kawakami, Y., Kato, R. M., Tabuchi, R., Tarakhovsky, A., Kawakami, T., Turck, C. W., Witte, O. N., and Rawlings, D. J. (2001) PKCbeta Modulates Antigen Receptor Signaling Via Regulation of Btk Membrane Localization. EMBO J. 20, 5692-5702.
72. Ruland, J., Duncan, G. S., Elia, A., del, B. B.,I, Nguyen, L., Plyte, S., Millar, D. G., Bouchard, D., Wakeham, A., Ohashi, P. S., and Mak, T. W. (2001) Bcl10 is a Positive Regulator of Antigen Receptor-Induced Activation of NF-kappaB and Neural Tube Closure. Cell. 104, 33-42.
73. McAllister-Lucas, L. M., Inohara, N., Lucas, P. C., Ruland, J., Benito, A., Li, Q., Chen, S., Chen, F. F., Yamaoka, S., Verma, I. M., Mak, T. W., and Nunez, G. (2001) Bimp1, a MAGUK Family Member Linking Protein Kinase C Activation to Bcl10-Mediated NF-kappaB Induction. J. Biol. Chem. 276, 30589-30597.
74. Ruefli-Brasse, A. A., French, D. M., and Dixit, V. M. (2003) Regulation of NF-kappaB-Dependent Lymphocyte Activation and Development by Paracaspase. Science. 302, 1581-1584.
75. Hara, H., Wada, T., Bakal, C., Kozieradzki, I., Suzuki, S., Suzuki, N., Nghiem, M., Griffiths, E. K., Krawczyk, C., Bauer, B., D'Acquisto, F., Ghosh, S., Yeh, W. C., Baier, G., Rottapel, R., and Penninger, J. M. (2003) The MAGUK Family Protein CARD11 is Essential for Lymphocyte Activation. Immunity. 18, 763-775.
76. Jun, J. E., Wilson, L. E., Vinuesa, C. G., Lesage, S., Blery, M., Miosge, L. A., Cook, M. C., Kucharska, E. M., Hara, H., Penninger, J. M., Domashenz, H., Hong, N. A., Glynne, R. J., Nelms, K. A., and Goodnow, C. C. (2003) Identifying the MAGUK Protein Carma-1 as a Central Regulator of Humoral Immune Responses and Atopy by Genome-Wide Mouse Mutagenesis. Immunity. 18, 751-762.
77. Newton, K., and Dixit, V. M. (2003) Mice Lacking the CARD of CARMA1 Exhibit Defective B Lymphocyte Development and Impaired Proliferation of their B and T Lymphocytes. Curr. Biol. 13, 1247-1251.
78. Egawa, T., Albrecht, B., Favier, B., Sunshine, M. J., Mirchandani, K., O'Brien, W., Thome, M., and Littman, D. R. (2003) Requirement for CARMA1 in Antigen Receptor-Induced NF-Kappa B Activation and Lymphocyte Proliferation. Curr. Biol. 13, 1252-1258.
79. Wang, D., Feng, J., Wen, R., Marine, J. C., Sangster, M. Y., Parganas, E., Hoffmeyer, A., Jackson, C. W., Cleveland, J. L., Murray, P. J., and Ihle, J. N. (2000) Phospholipase Cgamma2 is Essential in the Functions of B Cell and several Fc Receptors. Immunity. 13, 25-35.
80. Pappu, R., Cheng, A. M., Li, B., Gong, Q., Chiu, C., Griffin, N., White, M., Sleckman, B. P., and Chan, A. C. (1999) Requirement for B Cell Linker Protein (BLNK) in B Cell Development. Science. 286, 1949-1954.
81. Patke, A., Mecklenbrauker, I., Erdjument-Bromage, H., Tempst, P., and Tarakhovsky, A. (2006) BAFF Controls B Cell Metabolic Fitness through a PKC Beta- and Akt-Dependent Mechanism. J. Exp. Med. 203, 2551-2562.
82. Thuille, N., Gruber, T., Bock, G., Leitges, M., and Baier, G. (2004) Protein Kinase C Beta is Dispensable for TCR-Signaling. Mol. Immunol. 41, 385-390.
83. Volkov, Y., Long, A., and Kelleher, D. (1998) Inside the Crawling T Cell: Leukocyte Function-Associated Antigen-1 Cross-Linking is Associated with Microtubule-Directed Translocation of Protein Kinase C Isoenzymes Beta(I) and Delta. J. Immunol. 161, 6487-6495.
84. Chang, E. Y., Szallasi, Z., Acs, P., Raizada, V., Wolfe, P. C., Fewtrell, C., Blumberg, P. M., and Rivera, J. (1997) Functional Effects of Overexpression of Protein Kinase C-Alpha, -Beta, -Delta, -Epsilon, and -Eta in the Mast Cell Line RBL-2H3. J. Immunol. 159, 2624-2632.
85. Li, G., Lucas, J. J., and Gelfand, E. W. (2005) Protein Kinase C Alpha, betaI, and betaII Isozymes Regulate Cytokine Production in Mast Cells through MEKK2/ERK5-Dependent and -Independent Pathways. Cell. Immunol. 238, 10-18.
86. Cejas, P. J., Carlson, L. M., Zhang, J., Padmanabhan, S., Kolonias, D., Lindner, I., Haley, S., Boise, L. H., and Lee, K. P. (2005) Protein Kinase C betaII Plays an Essential Role in Dendritic Cell Differentiation and Autoregulates its Own Expression. J. Biol. Chem. 280, 28412-28423.
87. Hong, Y., Dumenil, D., van der Loo, B., Goncalves, F., Vainchenker, W., and Erusalimsky, J. D. (1998) Protein Kinase C Mediates the Mitogenic Action of Thrombopoietin in c-Mpl-Expressing UT-7 Cells. Blood. 91, 813-822.
88. Blume-Jensen, P., Siegbahn, A., Stabel, S., Heldin, C. H., and Ronnstrand, L. (1993) Increased Kit/SCF Receptor Induced Mitogenicity but Abolished Cell Motility After Inhibition of Protein Kinase C. EMBO J. 12, 4199-4209.
89. Rinaudo, M. S., Su, K., Falk, L. A., Halder, S., and Mufson, R. A. (1995) Human Interleukin-3 Receptor Modulates Bcl-2 mRNA and Protein Levels through Protein Kinase C in TF-1 Cells. Blood. 86, 80-88.
90. Xenaki, D., Pierce, A., Underhill-Day, N., Whetton, A. D., and Owen-Lynch, P. J. (2004) Bcr-Abl-Mediated Molecular Mechanism for Apoptotic Suppression in Multipotent Haemopoietic Cells: A Role for PKCbetaII. Cell. Signal. 16, 145-156.
91. Kawakami, T., Kawakami, Y., and Kitaura, J. (2002) Protein Kinase C Beta (PKC Beta): Normal Functions and Diseases. J. Biochem. 132, 677-682.
92. Formisano, P., Oriente, F., Fiory, F., Caruso, M., Miele, C., Maitan, M. A., Andreozzi, F., Vigliotta, G., Condorelli, G., and Beguinot, F. (2000) Insulin-Activated Protein Kinase Cbeta Bypasses Ras and Stimulates Mitogen-Activated Protein Kinase Activity and Cell Proliferation in Muscle Cells. Mol. Cell. Biol. 20, 6323-6333.
93. Bossenmaier, B., Mosthaf, L., Mischak, H., Ullrich, A., and Haring, H. U. (1997) Protein Kinase C Isoforms Beta 1 and Beta 2 Inhibit the Tyrosine Kinase Activity of the Insulin Receptor. Diabetologia. 40, 863-866.
94. Chin, J. E., Dickens, M., Tavare, J. M., and Roth, R. A. (1993) Overexpression of Protein Kinase C Isoenzymes Alpha, Beta I, Gamma, and Epsilon in Cells Overexpressing the Insulin Receptor. Effects on Receptor Phosphorylation and Signaling. J. Biol. Chem. 268, 6338-6347.
95. Farese, R. V., and Sajan, M. P. (2009) Metabolic Functions of Atypical Protein Kinase C: "Good and Bad". Am. J. Physiol. Endocrinol. Metab. .
96. Meier, M., Menne, J., and Haller, H. (2009) Targeting the Protein Kinase C Family in the Diabetic Kidney: Lessons from Analysis of Mutant Mice. Diabetologia. 52, 765-775.
97. Inoguchi, T., Battan, R., Handler, E., Sportsman, J. R., Heath, W., and King, G. L. (1992) Preferential Elevation of Protein Kinase C Isoform Beta II and Diacylglycerol Levels in the Aorta and Heart of Diabetic Rats: Differential Reversibility to Glycemic Control by Islet Cell Transplantation. Proc. Natl. Acad. Sci. U. S. A. 89, 11059-11063.
98. Wu, D., Peng, F., Zhang, B., Ingram, A. J., Kelly, D. J., Gilbert, R. E., Gao, B., and Krepinsky, J. C. (2009) PKC-beta1 Mediates Glucose-Induced Akt Activation and TGF-beta1 Upregulation in Mesangial Cells. J. Am. Soc. Nephrol. 20, 554-566.
99. Langham, R. G., Kelly, D. J., Gow, R. M., Zhang, Y., Cox, A. J., Qi, W., Thai, K., Pollock, C. A., Christensen, P. K., Parving, H. H., and Gilbert, R. E. (2008) Increased Renal Gene Transcription of Protein Kinase C-Beta in Human Diabetic Nephropathy: Relationship to Long-Term Glycaemic Control. Diabetologia. 51, 668-674.
100. Ishii, H., Jirousek, M. R., Koya, D., Takagi, C., Xia, P., Clermont, A., Bursell, S. E., Kern, T. S., Ballas, L. M., Heath, W. F., Stramm, L. E., Feener, E. P., and King, G. L. (1996) Amelioration of Vascular Dysfunctions in Diabetic Rats by an Oral PKC Beta Inhibitor. Science. 272, 728-731.
101. Koya, D., Jirousek, M. R., Lin, Y. W., Ishii, H., Kuboki, K., and King, G. L. (1997) Characterization of Protein Kinase C Beta Isoform Activation on the Gene Expression of Transforming Growth Factor-Beta, Extracellular Matrix Components, and Prostanoids in the Glomeruli of Diabetic Rats. J. Clin. Invest. 100, 115-126.
102. Koya, D., Haneda, M., Nakagawa, H., Isshiki, K., Sato, H., Maeda, S., Sugimoto, T., Yasuda, H., Kashiwagi, A., Ways, D. K., King, G. L., and Kikkawa, R. (2000) Amelioration of Accelerated Diabetic Mesangial Expansion by Treatment with a PKC Beta Inhibitor in Diabetic db/db Mice, a Rodent Model for Type 2 Diabetes. FASEB J. 14, 439-447.
103. Suzuma, K., Takahara, N., Suzuma, I., Isshiki, K., Ueki, K., Leitges, M., Aiello, L. P., and King, G. L. (2002) Characterization of Protein Kinase C Beta Isoform's Action on Retinoblastoma Protein Phosphorylation, Vascular Endothelial Growth Factor-Induced Endothelial Cell Proliferation, and Retinal Neovascularization. Proc. Natl. Acad. Sci. U. S. A. 99, 721-726.
104. Ohshiro, Y., Ma, R. C., Yasuda, Y., Hiraoka-Yamamoto, J., Clermont, A. C., Isshiki, K., Yagi, K., Arikawa, E., Kern, T. S., and King, G. L. (2006) Reduction of Diabetes-Induced Oxidative Stress, Fibrotic Cytokine Expression, and Renal Dysfunction in Protein Kinase Cbeta-Null Mice. Diabetes. 55, 3112-3120.
105. Meier, M., Park, J. K., Overheu, D., Kirsch, T., Lindschau, C., Gueler, F., Leitges, M., Menne, J., and Haller, H. (2007) Deletion of Protein Kinase C-Beta Isoform in Vivo Reduces Renal Hypertrophy but Not Albuminuria in the Streptozotocin-Induced Diabetic Mouse Model. Diabetes. 56, 346-354.
106. Griner, E. M., and Kazanietz, M. G. (2007) Protein Kinase C and Other Diacylglycerol Effectors in Cancer. Nat. Rev. Cancer. 7, 281-294.
107. Holler, C., Pinon, J. D., Denk, U., Heyder, C., Hofbauer, S., Greil, R., and Egle, A. (2009) PKCbeta is Essential for the Development of Chronic Lymphocytic Leukemia in the TCL1 Transgenic Mouse Model: Validation of PKCbeta as a Therapeutic Target in Chronic Lymphocytic Leukemia. Blood. 113, 2791-2794.
108. Murray, N. R., Davidson, L. A., Chapkin, R. S., Clay Gustafson, W., Schattenberg, D. G., and Fields, A. P. (1999) Overexpression of Protein Kinase C betaII Induces Colonic Hyperproliferation and Increased Sensitivity to Colon Carcinogenesis. J. Cell Biol. 145, 699-711.
109. Zhang, J., Anastasiadis, P. Z., Liu, Y., Thompson, E. A., and Fields, A. P. (2004) Protein Kinase C (PKC) betaII Induces Cell Invasion through a Ras/Mek-, PKC iota/Rac 1-Dependent Signaling Pathway. J. Biol. Chem. 279, 22118-22123.
110. Becker, K. P., and Hannun, Y. A. (2004) Isoenzyme-Specific Translocation of Protein Kinase C (PKC)betaII and Not PKCbetaI to a Juxtanuclear Subset of Recycling Endosomes: Involvement of Phospholipase D. J. Biol. Chem. 279, 28251-28256.
111. Hu, T., and Exton, J. H. (2004) Protein Kinase Calpha Translocates to the Perinuclear Region to Activate Phospholipase D1. J. Biol. Chem. 279, 35702-35708.
112. Becker, K. P., Kitatani, K., Idkowiak-Baldys, J., Bielawski, J., and Hannun, Y. A. (2005) Selective Inhibition of Juxtanuclear Translocation of Protein Kinase C betaII by a Negative Feedback Mechanism Involving Ceramide Formed from the Salvage Pathway. J. Biol. Chem. 280, 2606-2612.
113. Kitatani, K., Idkowiak-Baldys, J., and Hannun, Y. A. (2007) Mechanism of Inhibition of Sequestration of Protein Kinase C alpha/betaII by Ceramide. Roles of Ceramide-Activated Protein Phosphatases and phosphorylation/dephosphorylation of Protein Kinase C alpha/betaII on Threonine 638/641. J. Biol. Chem. 282, 20647-20656.
114. Graff, J. R., McNulty, A. M., Hanna, K. R., Konicek, B. W., Lynch, R. L., Bailey, S. N., Banks, C., Capen, A., Goode, R., Lewis, J. E., Sams, L., Huss, K. L., Campbell, R. M., Iversen, P. W., Neubauer, B. L., Brown, T. J., Musib, L., Geeganage, S., and Thornton, D. (2005) The Protein Kinase Cbeta-Selective Inhibitor, Enzastaurin (LY317615.HCl), Suppresses Signaling through the AKT Pathway, Induces Apoptosis, and Suppresses Growth of Human Colon Cancer and Glioblastoma Xenografts. Cancer Res. 65, 7462-7469.
115. Querfeld, C., Rizvi, M. A., Kuzel, T. M., Guitart, J., Rademaker, A., Sabharwal, S. S., Krett, N. L., and Rosen, S. T. (2006) The Selective Protein Kinase C Beta Inhibitor Enzastaurin Induces Apoptosis in Cutaneous T-Cell Lymphoma Cell Lines through the AKT Pathway. J. Invest. Dermatol. 126, 1641-1647.
116. Alugupalli, K. R. (2008) A Distinct Role for B1b Lymphocytes in T Cell-Independent Immunity. Curr. Top. Microbiol. Immunol. 319, 105-130.
117. Vos, Q., Lees, A., Wu, Z. Q., Snapper, C. M., and Mond, J. J. (2000) B-Cell Activation by T-Cell-Independent Type 2 Antigens as an Integral Part of the Humoral Immune Response to Pathogenic Microorganisms. Immunol. Rev. 176, 154-170.
|Science Writers||Nora G. Smart|
|Illustrators||Diantha La Vine|
|Authors||Carrie N. Arnold, Nathaniel Wang, Elaine Pirie, and Bruce Beutler|
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