|Mutation Type||critical splice donor site (2 bp from exon)|
|Coordinate||25,127,711 bp (GRCm38)|
|Base Change||T ⇒ C (forward strand)|
|Gene Name||dedicator of cytokinesis 8|
|Synonym(s)||A130095G14Rik, 5830472H07Rik, 1200017A24Rik|
|Chromosomal Location||24,999,529-25,202,432 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a member of the DOCK180 family of guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with Rho GTPases and are components of intracellular signaling networks. Mutations in this gene result in the autosomal recessive form of the hyper-IgE syndrome. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Jun 2010]
PHENOTYPE: Mice homozygous for inactivating mutations of this gene exhibit loss of marginal zone B cells, decrease in peritoneal B1 cells and peripheral naive T cells, failure of sustained antibody response after immunization, failure of germinal center persistence, and failure of B cell affinity maturation. [provided by MGI curators]
|Amino Acid Change|
|Institutional Source||Australian Phenomics Network|
|Gene Model||not available|
|Predicted Effect||probably benign|
|Meta Mutation Damage Score||Not available|
|Is this an essential gene?||Probably nonessential (E-score: 0.091)|
|Candidate Explorer Status||CE: no linkage results|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
Australian Phenome Bank: 34
|Last Updated||2019-05-26 8:08 AM by Diantha La Vine|
|Record Created||2010-12-30 10:21 AM by Nora G. Smart|
The captain morgan (cpm) and primurus (pri) mutations were identified while screening N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice for a failure to mount long-lived, high-affinity antibody responses despite a relatively normal initial wave of antibody production (1). These animals display normal initial antibody responses to both T-dependent and T-independent (nitrophenyl) antigens (Figure 1). However, during the mature phase of the antibody response, either after a booster immunization (44 days; Figure 1a) or without boosting (28 or 56 days after primary immunization; Figure 1b), immunoglobulin G (IgG) antibody to CGG failed to be sustained in pri/pri or cpm/cpm mice or in compound-heterozygous mice. The CGG immunogen carried a haptenic chemical group, azobenzenearsonate (ARS), which elicited appreciable antibody in wild type mice after 4 weeks (Figure 1b) due to the need for antibody hypermutation and affinity maturation (2;3). This response was also absent in Dock8 mutant mice (1).
A comprehensive analysis of B cell subsets in blood and primary and secondary lymphoid organs showed qualitatively normal development of circulating mature subsets but a near absence of marginal zone B (MZB) cells (Figure 2). The formation of immature B cells in the bone marrow and accumulation of mature follicular B cells seemed normal in mutant mice (Figure 2a,b), but there was profound deficiency of splenic MZB cells in cpm- and pri-homozygous mice and cpm/pri compound-heterozygous mice (Figure 2a-d), which was cell autonomous to B cells bearing the mutation in mixed chimeras (Figure 2e). MZB cell numbers were much higher in transgenic mice overexpressing the cytokine B cell activating factor (BAFF), but this failed to restore MZB cell formation by mutant cells. The frequency of B-1 cells in the peritoneal cavity was 60% lower in the mutant mice (Figure 2f), and this was cell autonomous in mixed chimeras. Analysis of splenic T cells showed normal numbers of activated or memory CD4+ and CD8+ T cells expressing high levels of the cluster of differentiation 44 marker (CD44hi) but a mean 50% lower number of naïve T cells in cpm- and pri-homozygous mice and in cpm/pri compound-heterozygous mice (CD44lo; Figure 2g). In 50:50 bone marrow chimeras with mutant T cells reconstituting in the presence of wild type T cells, T cells bearing the mutation had a cell-autonomous competitive disadvantage and comprised only 5% of the total peripheral T cells (Figure 2h) (1).
Further phenotypic analysis found that germinal centers (GCs), sites in lymph nodes and spleen where B cells undergo somatic hypermutation and antibody switching following immunization, are abnormally small in mice with mutations in Dock8 (Figure 3a). B cells bearing the Dock8 mutation contributed normally to the main subsets of B220+ (the B cell form of CD45; see the record for belittle) and IgD+ recirculating follicular B cells but contributed poorly to the B220+CD95+GL7+ GC subset, particularly at day 11 after immunization when the response has begun maturing (Figure 3c). The mutations therefore acted autonomously in individual B cells to interfere selectively with their capacity to differentiate into or sustain a GC state. These data suggest that Dock8 mutant B cells undergo normal T cell-dependent activation, switching and initial differentiation into GC cells in vivo, but are unable to persist or undergo affinity maturation. Dock8 mutant B cells display normal immunoglobulin gene hypermutation, but decreased survival and selection of higher-affinity IgG+ B cells (data not shown).
Dock8 mutant B cells also show disruption of immunological synapse (IS) organization. When B cells recognize antigen on cell membranes, B cell receptor (BCR) signaling triggers the integrin β2-containing LFA-1 (see the record for Joker) to bind strongly to its ligand intercellular adhesion molecule 1 (ICAM-1) on the antigen-presenting membrane, which promotes strong B cell adhesion and spreading (4). Both mutant and wild type cells adhered and clustered antigen into a central supramolecular cluster, but the mutant cells showed an inability to cluster ICAM-1 into a peripheral supramolecular cluster and consequently formed smaller areas of close membrane apposition (Figure 4a). Dock8 mutation had no effect on other BCR signaling events, including an increase in intracellular calcium stimulated by antibody to IgM (Figure 4b), induction of the activation markers CD25, CD86 and CD69 (Figure 4c), or cell division (Figure 4d). Dock8 mutant B cells are able to respond to normally to the activating molecule CD40 and lipopolysaccharide (LPS), which binds to Toll-like receptor 4 (TLR4; see the record for lps3). B cells from cpm/cpm and pri/pri mice interact normally with CD4+ T cells and migrate normally to lymph nodes (1), despite the dependency of the latter process on the adhesion of LFA-1 to ICAM-1 (5).
|Nature of Mutation|
The captain morgan mutation was mapped to Chromosome 19. Sequencing B cell–expressed transcripts in the minimal 4.5 Mb interval identified a T to C transition at position 25202201 in the Genbank genomic region NC_000085 for the Dock8 gene on chromosome 19 (GTAGAGGCC-> GCAGAGGCC). The mutation is located within the donor splice site of intron 20, two nucleotides from the previous exon. Dock8 contains 48 total exons. Sequencing of 74 cDNA clones from captain morgan splenocytes showed aberrant splicing between cryptic splice donors and the normal exon 21 splice acceptor to yield frameshifts and premature stop codons that completely eliminate the DHR2 domain of the DOCK8 protein. One of these aberrant transcripts is depicted below.
<--exon 19 <--exon 20 intron 20--> exon 21--> <--exon 21
734 -H--T--Q-………-G--Q--T- -G--R--G--L- -K--L--L-…………-C--Q--* 833
The donor splice site of intron 20, which is destroyed by the mutation, is indicated in blue; the mutated nucleotide is indicated in red; the new donor splice site is highlighted in gray.
The full-length mouse DOCK8 (dedicator of cytokinesis 8) protein is 2100 amino acids long, and is 92% identical to its human homologue (Figure 5). DOCK8 belongs to the DOCK180 superfamily of guanine nucleotide exchange factors (GEFs) that have been shown to activate members of the Rho family of small GTPases (6-9). In mammals, 11 of these proteins have been identified, and can be classified into four subfamilies; DOCK A (which includes DOCK2; see the record for frazz), DOCK B, DOCK C (which includes DOCK8 and DOCK7; see the record for moonlight) and DOCK D based on theirdiffering specificities for binding to the Rho GTPases Rac and Cdc42, regulatory domains,and associated subunits (6;8;9). DOCK A and B subfamilies activateRac, the DOCK D subfamily is specific for Cdc42, whereas theDOCK C subfamily has dual specificity for Rac and Cdc42 (6;7;10;11). Two domains are shared amongst all DOCK proteins, the catalytic DHR-2 (DOCK homology region 2) or CZH-2 (CDM-zizimin homology 2) domain and the DHR-1 or CZH-1 domain. The DHR-1 domain is located N-terminal to the DHR-2 domain (8;9). The sequences between the recognized domains are predicted to be mostly helical, and may fold as armadillo (ARM) repeat domains. The armadillo repeat is a roughly 40 amino acid long tandemly repeated sequence motif and forms suprahelical structures used to bind to other proteins, especially those containing the same motifs (12).
The DHR-2 domains of several DOCK family members interact with the nucleotide-free form of Rac and/or Cdc42 (8;9), and deletion of the DHR-2 domain in many of these proteins abolishes their ability to activate these GTPases (7;10;13;14). The DHR-2 domain is large domain containing roughly 450-550 amino acids, and is located at residues 1303-1824 in DOCK8. The zizimin 1/DOCK9 protein is able to dimerize through its DHR-2 domain (15), while structural analysis of DOCK9-Cdc42 complexes suggests that the presence of a nucleotide sensor contributes to release of guanine diphosphate (GDP) and subsequently, that of activated GTP-bound Cdc42 (Figure 6) (PDB 2WMO; 2WMN; 2WM9). Magnesium (Mg2+) exclusion, which promotes GDP release, is mediated by a conserved valine residue (Val 1986 in DOCK8) within the nucleotide sensor. Binding of GTP-Mg2+ to the nucleotide-free DOCK9/Cdc42 complex results in displacement of the sensor to allow discharge of GTP-bound Cdc42. The structure of the DHR-2 domain differs from that of other GEF catalytic domains and consists of three lobes A, B and C. The Cdc42 binding site and catalytic center are located in lobes B and C. Lobe A consists of an antiparallel array of five α helices (α1-α5) and stabilizes the DHR-2 domain through contacts with lobe B. DOCK9 dimerization occurs through helices 4 and 5. This interface contains residues that are conserved in other DOCK proteins (Lys 1754, Glu 1761, Arg 1764, Phe 1766, Leu 1769, His 1773, Leu 1776, Phe 1780, and Ile 1783 for DOCK8). Lobe B consists of two antiparallel β sheets arranged orthogonally, and lobe C comprises a four-helix bundle (α7-α10). The α10 helix is the most conserved region of the DHR-2 domain, and is interrupted by the seven-residue loop nucleotide sensor (16).
The roughly 250 amino acid DHR-1 domain (amino acids 329-571 in DOCK8) is not as well defined in these proteins. However, the DOCK A and B DHR-1 domains share weak homology to the C2 domain, a well characterized Ca2+-dependent lipid-binding module (17). Several DOCK proteins appear to be localized to the plasma membrane via interaction of the DHR-1 domain with phosphatidylinositol (3,5)-biphosphate (PIP2) and phosphatidylinositol (3,4,5) triphosphate (PIP3) signaling lipids (18-20). Other studies have shown that the DHR-1 domain for zizimin 1/DOCK9 is able to bind to the DHR-2 domain and inhibit its function (21). The structure of the DOCK180 (also known as DOCK1) DHR-1 domain confirms the similarity to C2 (Figure 7) (PDB 3L4C). The DHR-1 domain folds into a type II C2 domain fold consisting of an antiparallel β sandwich consisting of two four-stranded β sheets (β1- β8). The DHR-1 domain also contains three loops between β1-β2 (L1), β3-β4 (L2), and β5-β6 (L3) on the upper surface of the structure as well as two large insertions between β2 and β3 and β7 and β8. The loop region creates a positively charged pocket at the top of the molecule that allows recognition of the PIP3 head group. The pocket has many of the characteristics of lipid-binding pleckstrin homology (PH) domains. Residues in DOCK8 predicted to contact phospholipid are Lys 576, Arg 581, Tyr 641, His 642, His 652, Ser 654, Glu 666 and Lys 668, and mutagenesis of some of these residues in DOCK180 reduces or abolishes phospholipid binding. Unlike many C2 domains, the DHR-1 domain binds phospholipids independently of calcium. The DHR-1 domain also contains another highly basic pocket on its concave surface often called the β-groove in many C2 domains, but this does not participate in phospholipid binding (22).
The captain morgan mutation results in abnormal splicing of Dock8 causing premature truncation prior to the DHR2 domain.
In the mouse, Dock8 mRNA is expressed ten times more abundantly in B lymphocytes and T lymphocytes than in other cells (1) with high levels of expression in the spleen, lymph nodes and bone marrow (data from BioGPS). In humans, Northern blot analysis showed the presence of DOCK8 mRNA in placenta, lung, kidney and pancreas with low expression levels in the heart, brain and skeletal muscle (23). In the human immune system, DOCK8 mRNA is found in monocytes, B cells and T cells. High levels were found in activated primary T cell cultures and transformed lymphocyte lines (24). Human DOCK8 protein is expressed in peripheral blood mononuclear cells (PBMC) (25). DOCK8 expression is reduced in various human cancers (26;27).
DOCK8 protein localizes to the cytoplasm, but also accumulates in lamellipodia (23).
The Rho GTPases are known regulators of the actin cytoskeleton and affect multiple cellular activities including cell morphology, polarity, migration, proliferation and apoptosis, phagocytosis, cytokinesis, adhesion, vesicular transport, transcription and neurite extension and retraction (Figure 8). The Rho GTPases are active when bound to GTP and are inactive in their GDP-bound form [reviewed in (28)]. Regulation of Rho GTPase activity is complex and involves the guanine nucleotide exchange factors (GEFs) that promote the exchange of GDP for GTP, the GTPase-activating proteins (GAPs) that enhance the GTPase activity of Rho proteins, and the Rho guanine nucleotide-dissociation inhibitors (RhoGDIs) that sequester Rho GTPases in a GDP-bound state. GEFs that activate Rho GTPases can be divided into two main groups; the classical GEFs containing the nucleotide-exchanging Dbl-homology (DH) domain, and the DOCK180 superfamily, including DOCK7 (12).
The DOCK180 GEFs are also known as the CDM proteins, named for CED-5 (cell death abnormal 5), DOCK180, and 'Myoblast City' (MBC). CED-5 and MBC are the Caenorhabditis elegans and Drosophila melanogaster orthologues of DOCK180, respectively (9). Human DOCK180 was the first of these identified, and was cloned as a binding partner of Crk, which plays a role in signaling from focal adhesions (29). CED-5 was identified as a protein required for cell migration and phagocytosis (30), while MBC was identified as a protein essential for myoblast fusion and dorsal closure (31). All three of these molecules were found to be important for Rac activation and control of the actin cytoskeleton and microtubule dynamics. Rac GTPases are critical in generating actin-rich lamellipodial protusions that drive the movement of migrating cells. During this and similar processes, elevated levels of PIP3 are created at the leading edge by the local activity of phosphatidylinositol 3-kinase (PI3K), which promotes membrane attachment by DOCK complexes leading to polarized activation of Rac (6;10;18-20).
Three Rac isoforms have been identified in mammals, Rac1, Rac2 and Rac3. Rac1 is ubiquitously expressed and Rac3 is highly expressed in the brain, whereas Rac2 is largely restricted to the hematopoietic system (32). Rac2 -/- neutrophils (33), B cells (34) and T cells (35) show reduced migration and F-actin polymerization in response to chemokines, although chemotaxis is not completely abolished. Consistent with these observations, recruitment of Rac2 -/- neutrophils to sites of inflammation is impaired. Rac2-deficient mice also display a lack of peritoneal B-1 and MZB cells, as well as abnormal T-independent and T-dependent antibody responses (34). The incomplete block in chemotaxis most likely reflects the continued presence of Rac1 in these cell types. Deficiency in both Rac1 and Rac2 almost completely blocks B cell development and leads to defects in proliferation and survival (36), as well as preventing the formation of dendrites in mature dendritic cells (DCs), their polarized short-range migration toward T cells, and T cell priming (37). A human mutation in RAC2 causes neutrophil immunodeficiency syndrome (OMIM #608203), and decreases the numbers of peripheral T and B cells (38).
Deficiencies in other important cytoskeleton-regulating proteins also have immunological phenotypes. The DOCK180 GEF, DOCK2, functions downstream of chemokine heterotrimeric G-protein-coupled receptors to regulate Rac activation and migration of B and T lymphocytes, neutrophils, plasmacytoid dendritic cells (pDCs), and hematopoietic stem cells (19;39-42). Like Dock8 mutant mice, Dock2 -/- mice display a lack of MZB cells, and reduced numbers of mature CD4+ T cells, but also display defects in initial antibody production to both T-dependent and T-independent antigens and aberrant morphology of secondary lymphoid organs (SLO) due to the impaired homing of B and T lymphocytes to these tissues (34;39). MZB cell deficiency and aberrant antibody responses can also be found in mouse strains deficient in the cytoskeletal regulators Pyk2 (protein tyrosine kinase 2 beta) (43) and Lsc/p115 RhoGEF (44). Mice lacking the Rac GEFs Vav1 or Vav2 are defective in T cell maturation and function or B cell function including immunoglobulin class switching, ability to form GCs and generate antibody responses, respectively (45;46). The absence of both Vav1 and Vav2 causes a maturational block in the formation of B cells and defects in BCR signaling (46;47). Human immune deficiencies, such as Wiskott-Aldrich Syndrome (WAS; OMIM #301000) with mutations in the multi-domain WAS protein (WASp) and a T cell-deficient severe combined immunodeficiency due to lack of actin-regulating Coronin-1A, also involve lack of function of important cytoskeleton-regulating proteins (48;49). WASp contains a GTPasebinding site and interacts with activated Cdc42 (50). Similar to WAS patients, WASp-deficient mice exhibit decreased numbers of peripheral lymphocytes and impaired TCR activation (51). Mice lacking Coronin-1A display reduced numbers of peripheral T cells due to defects in T cell migration and increased rates of apoptosis (52).
During B cell activation, binding of antigen to the BCR initiates aggregation of BCR molecules, the recruitment of numerous intracellular signaling molecules and adapters into an assembly known as the signalosome, and the formation of the immunological synapse (IS), a structure that is also seen in activated T and natural killer (NK) cells (4;53;54). BCR signaling through multiple downstream signaling pathways lead to a multitude of responses including cell proliferation, differentiation, and apoptosis [reviewed by (55;56)]. These signals also lead to internalization and processing of antigen with major histocompatibility complex (MHC) molecules and presentation of these complexes on the B cell surface leading to the recruitment of CD4+ helper T cells. During a T cell-dependent humoral immune response, CD4+ T helper cell subsets including TFH, Th1 and Th2 cells migrate to the T cell/B cell borders in SLO, and interact with cognate antigen-specific B cells through the pairing of T cell and B cell surface ligands and receptors such as CD40 with its ligand (see the record for walla). This interaction results in the secretion by T helper cells of certain cytokines known to promote B cell survival, proliferation, and antibody production (57;58). Once activated, B cells differentiate to form extrafollicular plasma cells capable of the rapid secretion of low-affinity antibodies or they enter into GCs in the lymph node and spleen to undergo affinity maturation and generate extremely high-affinity antibodies and long-lasting memory cells (57). Rearrangements of the actin cytoskeleton in B cells are critical for many of these processes including BCR clustering, formation of the IS, antigen internalization and in cooperation with clathrin to mediate efficient attenuation of BCR signaling (4;59-61). The BCR signaling molecules Vav and phospholipase C γ2 (PLC-γ2; see the record for queen) are critical for IS formation (62) and PLC-γ2 is recruited to the plasma membrane by PI3K-produced PIP3 (56).
In humans, DOCK8 deficiency results in an autosomal recessive form of hyper-IgE recurrent infection syndrome (HIES; OMIM #243700) (24;25). Autosomal dominant HIES is characterized by recurrent Staphylococcus aureus skin abscesses, increased serum IgE, and abnormalities of the connective tissue, skeleton, and dentition (63). The autosomal recessive form shares hyper-IgE, eosinophilia, and recurrent Staphylococcal infections, but is distinguished from autosomal dominant HIES by the lack of connective tissue and skeletal involvement (64). Autosomal dominant HIES is caused by mutations in STAT3 (signal transducer and activator of transcription 3) (65), which encodes a protein that is activated by various cytokines and growth factors. In addition to homozygous or compound heterozygous mutations in DOCK8, autosomal recessive HIES is also caused by non-receptor tyrosine-protein kinase TYK2 deficiency (66). TYK2, along with the protein kinase JAK, is critical for activating STAT proteins downstream of multiple signaling pathways (67). Patients with DOCK8 deficiency are unusually susceptible to viral infections and virally-caused cancers. Reduced numbers of T, B, and NK cells have been reported along with a selective defect in CD8+ T cell activation (24). However, another study suggests most patients have normal numbers of B and NK cells, a greater decrease in the CD4+ T cell population than the CD8+ T cell population, and a more comprehensive T cell activation defect involving both T cell subsets (25). Both autosomal dominant and autosomal recessive HIES are linked to a lack of Th17 cell function including the failure to produce the interleukin 17 (IL-17) cytokine (68). Th17 are a subset of CD4+ T helper cells that play an important role in the development of autoimmune diseases like rheumatoid arthritis, as well as being critical in the clearance of fungal and extracellular bacterial infections (69).
The relatively normal initiation of antibody production by mice with Dock8 mutations suggests that the extrafollicular B cell clonal expansion, plasma cell formation and immunoglobulin class switching, which depends on interactions with T helper cells, is intact. However, subsequent antibody responses and affinity maturation occurring in the GCs is significantly impaired. This defect may be compounded by the lower number of CD4+ helper T cells in Dock8 mutant mice, although mixed-chimera and adoptive-transfer studies clearly establish that the mutation profoundly cripples the persistence and affinity maturation of mutant GC B cells even in the presence of a normal complement of helper T cells (1).
Like DOCK2, DOCK8 is likely to regulate the activity of GTPases and thus be involved in cytoskeletal changes associated with various cellular processes. Transient transfection of a C-terminal fragment of DOCK8 containing the DHR-2 domain resulted in formation of vesicular structures in cells, suggesting that DOCK8 may play a role in the organization of filamentous actin (23). Regulation of the actin cytoskeleton by DOCK8 may explain the defect in formation of the B cell IS in mediating integrin clustering following BCR signaling in Dock8 mutant B cells. The T cell defects seen in human patients with DOCK8 mutations suggests that DOCK8 may also regulate the formation of the IS in T cells. The role of integrins in lowering the threshold of B cell activation (4;70) is thought to be particularly important during later stages of affinity maturation in the GCs, where B cells are competing for limited amounts of antigen on the surface of follicular dendritic cells (FDCs). In addition, the integrin-dependent binding of the heavy chain of the CD98 membrane protein has been shown to be required for the proliferative burst of B cells that occurs in GCs necessary for adaptive immunity (71). The requirement for DOCK8 in IS formation is very similar to defects in B cell formation of peripheral supramolecular clusters caused by mutations in Rac2 or Vav1 and Vav2 (72). Compared with those proteins or with DOCK2, DOCK8 seems to have a more restricted function for BCR-integrin coordination, because follicular B cell development, migration, chemotaxis, activation and T cell–independent type 2 antibody responses are normal in Dock8 mutant B cells. In addition, DOCK8 does not affect other BCR signaling events unlike Rac2 and Vav (1). Interestingly, the WASp protein also appears to be specifically required for clustering of LFA-1 during formation of the mature IS in B cells, with no effects on downstream BCR signaling (51;73).
The humoral immunodeficiency in mice caused by Dock8 mutation closely resembles that resulting from mutations in the gene encoding the BCR coreceptor CD19, which is phosphorylated by BCR engagement and subsequently recruits PI3K (74). In humans, CD19 mutations result in common variable immunodeficiency 3 (CVID3; OMIM #613493). Patients with CVID3 have normal numbers of IgD+ recirculating B cells and presence of GCs, but low numbers of CD27+ memory B cells and low-avidity antibody to rabies vaccine (75). Like Dock8 mutant mice, mice lacking CD19 have normal numbers of peripheral B cells, calcium responses and proliferation in response to BCR activation, T-independent antibody responses, initiation of GCs and immunoglobulin switching, but lack MZB cells and have a limited expansion of GCs with failure of affinity maturation or long-lived antibody(76-78). The smaller GC size and loss of MZB cells in Cd19 mutant mice are rescued by a mutation in Pten (encoding the PIP3 phosphatase), emphasizing the involvement of PIP3 and PI3K in these processes (79). However, lack of CD19 function greatly diminishes the early step of B cell adhesion and clustering (80), whereas DOCK8 deficiency disrupts the later step of peripheral supramolecular cluster formation (1). This may be due to the recruitment of other BCR signaling molecules by CD19, in addition to PI3K (81). The phenotypic similarities and the fact that DOCK proteins are recruited by PIP3 to the membrane to activate Rac at sites of PI3K activation (9) suggest that DOCK8 serves as an effector downstream of CD19 and PI3K to promote G protein signaling events critical for integrin polarization at the synapse and for the survival of MZB cells and GC B cells. MZB cells are highly dependent on both BCR-CD19-PI3K signaling (78;82-84) and integrin signaling (43;85). Coordinated signaling by BCR and integrins has also been proposed as being critical for GC B cell survival and selection, as ICAM-1 has high expression on FDCs presenting antigen in GCs and inhibits apoptosis of GC B cells in vitro(86).
The captain morgan mutation is likely to be a functional null as the transcripts produced by aberrant splicing of the Dock8 gene result in premature truncation prior to the GTPase activating DHR2 domain. The phenotypes of captain morgan animals are identical to those found in primurus mice with a point mutation in the DHR2 domain.
|Primers||Primers cannot be located by automatic search.|
Genotyping protocols are from the Australian PhenomeBank.
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19. Kunisaki, Y., Nishikimi, A., Tanaka, Y., Takii, R., Noda, M., Inayoshi, A., Watanabe, K., Sanematsu, F., Sasazuki, T., Sasaki, T., and Fukui, Y. (2006) DOCK2 is a Rac Activator that Regulates Motility and Polarity during Neutrophil Chemotaxis. J. Cell Biol.. 174, 647-652.
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|Science Writers||Nora G. Smart|
|Illustrators||Diantha La Vine|
|Authors||Katrina L Randall, Teresa Lambe, Andy L Johnson, Bebhinn Treanor, Edyta Kucharska, Heather Domaschenz, Belinda Whittle, Lina E Tze, Anselm Enders, Tanya L Crockford, Tiphaine Bouriez-Jones, Duncan Alston, Jason G Cyster, Michael J Lenardo, Fabienne Mackay, Elissa K Deenick, Stuart G Tangye, Tyani D Chan, Tahra Camidge, Robert Brink, Carola G Vinuesa, Facundo D Batista, Richard J Cornall, Christopher C Goodnow|