|List |< first << previous [record 17 of 511] next >> last >||
|Coordinate||101,702,776 bp (GRCm38)|
|Base Change||A ⇒ T (forward strand)|
|Gene Name||phosphatidylinositol 3-kinase, regulatory subunit, polypeptide 1 (p85 alpha)|
|Synonym(s)||p55alpha, p85alpha, PI3K, p50alpha|
|Chromosomal Location||101,680,563-101,768,217 bp (-)|
|MGI Phenotype||Homozygotes for a targeted null mutation exhibit perinatal lethality associated with hepatic necrosis, chylous ascites, enlarged muscle fibers, calcification of cardiac tissue, and hypoglycemia. Mutants lacking only the major isoform are immunodeficient.|
|Amino Acid Change||Tyrosine changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000056774]|
AA Change: Y189*
|Predicted Effect||probably null|
|Phenotypic Category||decrease in B cells, decrease in B:T cells, decrease in B1a cells in B1 cells, decrease in IgD+ B cells, decrease in IgM+ B cells, increase in CD4+ T cells, increase in CD8+ T cells, increase in IgE response to a Cysteine Protease (Papain), increase in OVA-specific IgE, increase in T cells|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Sperm, gDNA|
|Last Updated||12/08/2016 10:05 AM by Katherine Timer|
|Record Created||02/28/2016 5:35 PM|
The anubis phenotype was identified among G3 mice of the pedigree R2474, some of which showed a decrease in the B to T cell ratio (Figure 1) due to a decrease in the frequency of total B cells (Figure 2), B1a cells in B1 cells (Figure 3), IgD+ B cells (Figure 4), and IgM+ B cells (Figure 5) with a concomitant increase in the frequency of total T cells (Figure 6), including CD4+ T cells (Figure 7) and CD8+ T cells (Figure 8), all in the peripheral blood.
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 31 mutations. All of the above anomalies were linked by continuous variable mapping to two mutations on chromosome 13 in genes Pik3r1 and Parp8. The mutation in Pik3r1 is presumed to be causative as mutations in Pik3r1 cause immunodeficiency in the mouse [see MGI for a list of Pik3r1 alleles; (1;2)]. The Pik3r1 mutation is a T to A transversion at base pair 101,702,776 (v38) on chromosome 13, or base pair 65,442 in the GenBank genomic region NC_000079 encoding Pik3r1. The strongest association was found with a recessive model of linkage to the normalized frequency of total T cells in the peripheral blood, wherein one variant homozygote departed phenotypically from four homozygous reference mice and seven heterozygous mice with a P value of 2.379 x 10-7 (Figure 9).
The mutation corresponds to residue 1,188 in the mRNA sequence NM_001077495 within exon 5 of 16 total exons.
The mutated nucleotide is indicated in red. The mutation results in a substitution of tyrosine 189 to a premature stop codon (Y189*) in the p85α protein; p55α and p50α are not affected.
Pik3r1 encodes p85α, a regulatory subunit of class IA phosphatidylinositol 3-kinases (PI3Ks). To form a functional class I PI3K, a p110 catalytic subunit forms a heterodimer with a p85 regulatory subunit (3;4). There are three class IA p110 subunits (p110α, p110β, and p110δ [see the record for stinger]) encoded by Pik3ca, Pik3cb, and Pik3cd, respectively, and one class IB p110 subunit, p110γ (encoded by Pik3cg). Five class IA regulatory subunits are encoded by three distinct genes (Pik3r1 (p85α, p55α, p50α), Pik3r2 (p85β) and Pik3r3 (p55γ); p85α, p55α, and p50α are splice variants of Pik3r1 (Figure 10) (5-7). In activated cells, the p85 subunit recruits the p110 subunit to the plasma membrane and activates it (7-9). Conversely, the p85 subunit also inhibits the enzymatic activity of the p110 subunit in quiescent cells (10). The p85 subunits also mediate the interactions of the PI3Ks with the cytoplasmic domains of receptors as well as with adaptor proteins (11). p85α has several binding partners that mediate several functions, including PI3K activation, cell signaling, and cell adhesion. For a comprehensive list of p85α binding partners see Table 1 in (12).
The p55α and p50α isoforms have two SH2 (Src homology 2) domains [nSH2 (N-terminal SH2 domain) and cSH2 (C-terminal SH2 domain)] and a p110-binding domain [iSH2 (inter SH2 domain)]. The splicing of the two variants is the same, but the p55α isoform is two amino acids longer than p50α (13). The nSH2 and cSH2 domains bind to pYxxM motifs (where pY is phosphorylated tyrosine) on several proteins namely activated receptor tyrosine kinases (e.g., PDGFR and EGFR) and adaptor proteins (e.g., (e.g. IRS-1 (14), Grb2, Gab1/2 (GRB2-associated binding protein 2) (15), Shc (16), Crk-L (17) and β-catenin (18)). The interactions between p85α and these proteins derepresses p110 activity and promtes the localization of p85—p110 to the plasma membrane. In addition to binding the p110 subunit, the iSH2 domain binds α/β- and γ-tubulins, which function in vesicle trafficking (α/β-tubulin) and in the microtubule-organizing center in centrosomes (γ-tubulin) (19). The interaction between p85α and the tubulins is proposed to regulate budding or vesicle fusion.
The p85α isoform has the nSH2, cSH2, and iSH2 domains, but also has a SH3 domain at the N-terminus (amino acids 6-78) and a RhoGAP domain (amino acids 126-298). Between the SH3 and RhoGAP domain and between the RhoGAP and nSH2 domain are proline-rich regions. The SH3 domain binds proline-rich target sequences (e.g., PxxP motifs). p85α can interact with other p85α proteins through the SH3 domains to form homodimers (20). The formation of p85α homodimers is proposed to mask the SH3, proline-rich, and RhoGAP domains until the dimer is disrupted. The interaction between the p85α SH3 domain and its target proteins regulates PI3K activity (21;22), and can also couple CD28 receptor endocytosis with actin polymerization (23). The p85α proline-rich regions bind to the SH3 domains of several target proteins, including Grb2 (24), Crk (25), α-actinin (26), Abl, and the Src family kinases (27-29). The RhoGAP domain shares homology with GAP domains in the Rac/Rho/Cdc42 family of GTPases, which regulate actin dynamics in cell migration, cytokinesis, and vesicle trafficking (30). GAP proteins stimulate GTP hydrolysis of G proteins to switch them from an active GTP-bound conformation to an inactive GDP-bound state. p85α binds to the GTP forms of Rac1 and Cdc42, leading to PI3K activation, but p85α does not exert GAP activity at physiological levels in the cell (31;32). p85α has GAP activity towards Rab4 and Rab5 (33;34); Rab4 and Rab5 are GTPases that regulate receptor tyrosine kinase trafficking (35). The RhoGAP domain of p85α binds and positively regulates PTEN, a phosphatase that negatively regulates PI3K activity (36). PTEN dephosphorylates PtdIns(3,4,5)P3 lipids at the 3-position to prevent further activation of downstream Akt signaling.
p85α undergoes several posttranslational modifications including phosphorylation. The p110 subunit can phosphorylate p85α on Ser608, subsequently reducing p85-p110 activity (37). p85α is also phosphorylated on Ser83 by protein kinase A (PKA), leading to increased PI3K-mediated Ras binding and PI3K activation (38). Tyr688 is phosphorylated by Abl and Src family tyrosine kinases, which putatively alters the SH2 binding properties of p85α and reduces the inhibition of p85α on p110, subsequently resulting in PI3K activation (39;39;40;40). Tyr508 is phosphorylated by the PDGFR (41) and in response to IL-8 and/or GM-CSF. The affect of Tyr508 phosphorylation is unknown. p85α is dephosphorylated by SHP-1 and CD148 (39;42). p85α can be ubiquitinated by Cbl-b. p85α ubiquitination does not induce p85α degradation, but prevents p85α recruitment to the T cell receptor co-receptor, CD28 (43).
The anubis mutation results in a substitution of tyrosine 189 to a premature stop codon (Y189*) within the RhoGAP domain.
Pik3r1 is ubiquitously expressed in the mouse (BioGPS). The p85α and p50α mRNAs are most abundant in the liver, and the p85α, p55α, and p50α mRNAs is also highly expressed in the brain and kidney (13). The p85α protein was highly expressed in every rat tissue examined (6;13). The p55α and p50α proteins were highly expressed in the brain, liver, and kidney; p55α, and p50α were expressed at low levels in fat and muscle (13).
PI3Ks are highly conserved lipid signaling kinases. The PI3Ks are divided into class I, II, or III based on their molecular structure, regulation, and in vivo substrate specificities [reviewed in (11;44)]. Class I PI3Ks include class IA and class IB PI3K subclasses; class IA PI3Ks are typically activated downstream of tyrosine kinase-linked receptors, while class IB PI3Ks are activated downstream of G protein-coupled receptors [reviewed in (11)].
After cell stimulation by growth factors, hormones, cytokines, or antigens, the PI3Ks are recruited to the inner face of the plasma membrane where they phosphorylate phosphatidylinositol (PtdIns), PtdIns 4-phosphate, and/or PtdIns-4,5-bisphosphate (PtdIns(4,5)P2; PIP2) at the D3 position of the inositol ring, generating their respective D3’ phosphorylated derivatives [e.g., PIP2 phosphorylation generates the second messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3; PIP3); (4;45); reviewed in (11;44); Figure 11]. PIP3 recruits downstream signaling proteins to the plasma membrane including the serine-threonine kinases Akt (alternatively, protein kinase B [PKB]) and phosphoinositide-dependent kinase 1 (PDK1) as well as Tec family tyrosine kinases and exchange factors that regulate heterotrimeric guanosine triphosphate (GTP)-binding proteins such as Vav, PLCγ1, and PLCγ2 (see the record for queen) [(4); reviewed in (11;44)]. Subsequently, activation of downstream targets (e.g., Rac1, p21-activated kinase 1 [PAK1], MEK, ERK1, and ERK2) mediates several cellular processes including growth, proliferation, differentiation, survival, apoptosis, adhesion, and migration [(46); reviewed in (44)]. PI3K-associated signaling can be antagonized by PTEN (phosphatase and tensin homologue deleted on chromosome 10) and SHIP (SH2-containing inositol phosphatase), lipid phosphatases that dephosphorylate PIP3 on the D3 and D5 positions, respectively [reviewed in (47)]. For more information on the PI3K signaling pathway, please see the record for sothe and stinger.
PIK3R1 mutations are linked to immunodeficiency-36 (IMD36; OMIM: #616005; (48)), agammalobulinemia-7 (AGM7; OMIM: #615214; (49)), and SHORT (Short stature, Hyperextensible joints, Ocular depression, Rieger anomaly, and Teeth delay) syndrome (OMIM: #269880; (50;51)). Patients with IMD36 exhibited recurrent respiratory infections and bacterial infections (48). None of the patients had symptoms of allergy, autoimmunity, splenomegaly, or lymphadenopathy (48). The patients had decreased numbers of naïve CD4+ and CD8+ T cells; one patient had decreased numbers of memory B cells (48). All IMD36 patients exhibited impaired B cell function with hypogammaglobulinemia (48). A patient with AGM7 exhibited defects in early B cell development and developed juvenile idiopathic arthritis, erythema nodosum, and inflammatory bowel disease (49). Patients with SHORT syndrome exhibit a range of clinical phenotypes (see the description of the acryonym). PIK3R1 mutations are observed at high frequency (20%) in endometrial cancer (52).
Pik3r1-deficient (Pik3r1-/-) mice exhibit perinatal lethality by postnatal day 7 (53;54). The Pik3r1-/- mice had hepatocyte necrosis, chylous ascites, enlarged skeletal muscle fibers, brown fat necrosis, and cardiac tissue calcification. Mice with selective deletion of p85α (p85α-/-) are viable (55). The p85α-/- mice have increased expression of the p55α and p50α isoforms. In the p85α-/- mice, the p50α can bind p110 to partially compensate for the loss of p85α (55). The Pik3r1-/- and p85α-/- mice have increased glucose uptake and insulin sensitivity (53;55). Mice with selective deletion of the p55α and p50α isoforms (p55α/p50α-/-) are viable and maintain normal blood glucose levels, but have lower fasting insulin levels (56). The p55α/p50α-/- mice exhibited increased insulin sensitivity and increased insulin-stimulated glucose transport in extensor digitorum longus muscle tissues and adipocytes.
Pik3r1-/- chimeric mice (using a Rag2-deficient blastocyst complementation system) had reduced numbers of peripheral blood mature B cells and reduced serum levels of IgM, IgG1, IgG2a, IgG3, and IgA (54). The remaining B cells exhibited reduced proliferative responses after exposure to anti-IgM, anti-CD40, and lipopolysaccharide; T cell development and proliferative responses were normal. The anubis mice exhibited defects in T cell development similar to patients with IMD36 (48), but in contrast to the Pik3r1-/- chimeric mice (54). The immune phenotypes in the anubis mice indicate that the p85αanubis exhibits loss-of-function. Some PI3K function may be rescued by the expression of intact p55α and p50α in the anubis mice. Intact p55 and p50 should be present precluding the prescence of metabolic effects described previously.
anubis(F):5'- TTCTCACTTGGGCAGGCTTC -3'
anubis(R):5'- GTCAGTGTGCCATGCTTCTG -3'
anubis_seq(F):5'- CAATAGGGTGTCTTCTATCAGATGC -3'
anubis_seq(R):5'- CAGTGTGCCATGCTTCTGTTCTG -3'
1. Suzuki, H., Terauchi, Y., Fujiwara, M., Aizawa, S., Yazaki, Y., Kadowaki, T., and Koyasu, S. (1999) Xid-Like Immunodeficiency in Mice with Disruption of the p85alpha Subunit of Phosphoinositide 3-Kinase. Science. 283, 390-392.
2. Dai, X., Chen, Y., Schuman, J., Hua, Z., Adamson, J. W., Wen, R., and Wang, D. (2006) Distinct Roles of Phosphoinositide-3 Kinase and Phospholipase Cgamma2 in B-Cell Receptor-Mediated Signal Transduction. Mol Cell Biol. 26, 88-99.
3. Chantry, D., Vojtek, A., Kashishian, A., Holtzman, D. A., Wood, C., Gray, P. W., Cooper, J. A., and Hoekstra, M. F. (1997) P110delta, a Novel Phosphatidylinositol 3-Kinase Catalytic Subunit that Associates with P85 and is Expressed Predominantly in Leukocytes. J Biol Chem. 272, 19236-19241.
4. Senis, Y. A., Atkinson, B. T., Pearce, A. C., Wonerow, P., Auger, J. M., Okkenhaug, K., Pearce, W., Vigorito, E., Vanhaesebroeck, B., Turner, M., and Watson, S. P. (2005) Role of the p110delta PI 3-Kinase in Integrin and ITAM Receptor Signalling in Platelets. Platelets. 16, 191-202.
5. Ueki, K., Algenstaedt, P., Mauvais-Jarvis, F., and Kahn, C. R. (2000) Positive and Negative Regulation of Phosphoinositide 3-Kinase-Dependent Signaling Pathways by Three Different Gene Products of the p85alpha Regulatory Subunit. Mol Cell Biol. 20, 8035-8046.
6. Inukai, K., Anai, M., Van Breda, E., Hosaka, T., Katagiri, H., Funaki, M., Fukushima, Y., Ogihara, T., Yazaki, Y., Kikuchi, Oka, Y., and Asano, T. (1996) A Novel 55-kDa Regulatory Subunit for Phosphatidylinositol 3-Kinase Structurally Similar to p55PIK is Generated by Alternative Splicing of the p85alpha Gene. J Biol Chem. 271, 5317-5320.
7. Jimenez, C., Hernandez, C., Pimentel, B., and Carrera, A. C. (2002) The p85 Regulatory Subunit Controls Sequential Activation of Phosphoinositide 3-Kinase by Tyr Kinases and Ras. J Biol Chem. 277, 41556-41562.
8. Glassford, J., Vigorito, E., Soeiro, I., Madureira, P. A., Zoumpoulidou, G., Brosens, J. J., Turner, M., and Lam, E. W. (2005) Phosphatidylinositol 3-Kinase is Required for the Transcriptional Activation of Cyclin D2 in BCR Activated Primary Mouse B Lymphocytes. Eur J Immunol. 35, 2748-2761.
9. Yu, J., Zhang, Y., McIlroy, J., Rordorf-Nikolic, T., Orr, G. A., and Backer, J. M. (1998) Regulation of the p85/p110 Phosphatidylinositol 3'-Kinase: Stabilization and Inhibition of the p110alpha Catalytic Subunit by the p85 Regulatory Subunit. Mol Cell Biol. 18, 1379-1387.
10. Fransson, S., Uv, A., Eriksson, H., Andersson, M. K., Wettergren, Y., Bergo, M., and Ejeskar, K. (2012) P37delta is a New Isoform of PI3K p110delta that Increases Cell Proliferation and is Overexpressed in Tumors. Oncogene. 31, 3277-3286.
11. Vanhaesebroeck, B., Leevers, S. J., Ahmadi, K., Timms, J., Katso, R., Driscoll, P. C., Woscholski, R., Parker, P. J., and Waterfield, M. D. (2001) Synthesis and Function of 3-Phosphorylated Inositol Lipids. Annu Rev Biochem. 70, 535-602.
12. Mellor, P., Furber, L. A., Nyarko, J. N., and Anderson, D. H. (2012) Multiple Roles for the p85alpha Isoform in the Regulation and Function of PI3K Signalling and Receptor Trafficking. Biochem J. 441, 23-37.
13. Inukai, K., Funaki, M., Ogihara, T., Katagiri, H., Kanda, A., Anai, M., Fukushima, Y., Hosaka, T., Suzuki, M., Shin, B. C., Takata, K., Yazaki, Y., Kikuchi, M., Oka, Y., and Asano, T. (1997) P85alpha Gene Generates Three Isoforms of Regulatory Subunit for Phosphatidylinositol 3-Kinase (PI 3-Kinase), p50alpha, p55alpha, and p85alpha, with Different PI 3-Kinase Activity Elevating Responses to Insulin. J Biol Chem. 272, 7873-7882.
14. Sun, X. J., Rothenberg, P., Kahn, C. R., Backer, J. M., Araki, E., Wilden, P. A., Cahill, D. A., Goldstein, B. J., and White, M. F. (1991) Structure of the Insulin Receptor Substrate IRS-1 Defines a Unique Signal Transduction Protein. Nature. 352, 73-77.
15. Sattler, M., Mohi, M. G., Pride, Y. B., Quinnan, L. R., Malouf, N. A., Podar, K., Gesbert, F., Iwasaki, H., Li, S., Van Etten, R. A., Gu, H., Griffin, J. D., and Neel, B. G. (2002) Critical Role for Gab2 in Transformation by BCR/ABL. Cancer Cell. 1, 479-492.
16. Harrison-Findik, D., Susa, M., and Varticovski, L. (1995) Association of Phosphatidylinositol 3-Kinase with SHC in Chronic Myelogeneous Leukemia Cells. Oncogene. 10, 1385-1391.
17. Sattler, M., Salgia, R., Okuda, K., Uemura, N., Durstin, M. A., Pisick, E., Xu, G., Li, J. L., Prasad, K. V., and Griffin, J. D. (1996) The Proto-Oncogene Product p120CBL and the Adaptor Proteins CRKL and c-CRK Link c-ABL, p190BCR/ABL and p210BCR/ABL to the Phosphatidylinositol-3' Kinase Pathway. Oncogene. 12, 839-846.
18. Woodfield, R. J., Hodgkin, M. N., Akhtar, N., Morse, M. A., Fuller, K. J., Saqib, K., Thompson, N. T., and Wakelam, M. J. (2001) The p85 Subunit of Phosphoinositide 3-Kinase is Associated with Beta-Catenin in the Cadherin-Based Adhesion Complex. Biochem J. 360, 335-344.
19. Kapeller, R., Toker, A., Cantley, L. C., and Carpenter, C. L. (1995) Phosphoinositide 3-Kinase Binds Constitutively to alpha/beta-Tubulin and Binds to Gamma-Tubulin in Response to Insulin. J Biol Chem. 270, 25985-25991.
20. Harpur, A. G., Layton, M. J., Das, P., Bottomley, M. J., Panayotou, G., Driscoll, P. C., and Waterfield, M. D. (1999) Intermolecular Interactions of the p85alpha Regulatory Subunit of Phosphatidylinositol 3-Kinase. J Biol Chem. 274, 12323-12332.
21. Guinebault, C., Payrastre, B., Racaud-Sultan, C., Mazarguil, H., Breton, M., Mauco, G., Plantavid, M., and Chap, H. (1995) Integrin-Dependent Translocation of Phosphoinositide 3-Kinase to the Cytoskeleton of Thrombin-Activated Platelets Involves Specific Interactions of p85 Alpha with Actin Filaments and Focal Adhesion Kinase. J Cell Biol. 129, 831-842.
22. Gout, I., Middleton, G., Adu, J., Ninkina, N. N., Drobot, L. B., Filonenko, V., Matsuka, G., Davies, A. M., Waterfield, M., and Buchman, V. L. (2000) Negative Regulation of PI 3-Kinase by Ruk, a Novel Adaptor Protein. EMBO J. 19, 4015-4025.
23. Badour, K., McGavin, M. K., Zhang, J., Freeman, S., Vieira, C., Filipp, D., Julius, M., Mills, G. B., and Siminovitch, K. A. (2007) Interaction of the Wiskott-Aldrich Syndrome Protein with Sorting Nexin 9 is Required for CD28 Endocytosis and Cosignaling in T Cells. Proc Natl Acad Sci U S A. 104, 1593-1598.
24. Wang, J., Auger, K. R., Jarvis, L., Shi, Y., and Roberts, T. M. (1995) Direct Association of Grb2 with the p85 Subunit of Phosphatidylinositol 3-Kinase. J Biol Chem. 270, 12774-12780.
25. Gelkop, S., Babichev, Y., and Isakov, N. (2001) T Cell Activation Induces Direct Binding of the Crk Adapter Protein to the Regulatory Subunit of Phosphatidylinositol 3-Kinase (p85) Via a Complex Mechanism Involving the Cbl Protein. J Biol Chem. 276, 36174-36182.
26. Shibasaki, F., Fukami, K., Fukui, Y., and Takenawa, T. (1994) Phosphatidylinositol 3-Kinase Binds to Alpha-Actinin through the p85 Subunit. Biochem J. 302 ( Pt 2), 551-557.
27. Liu, X., Marengere, L. E., Koch, C. A., and Pawson, T. (1993) The v-Src SH3 Domain Binds Phosphatidylinositol 3'-Kinase. Mol Cell Biol. 13, 5225-5232.
28. Prasad, K. V., Janssen, O., Kapeller, R., Raab, M., Cantley, L. C., and Rudd, C. E. (1993) Src-Homology 3 Domain of Protein Kinase p59fyn Mediates Binding to Phosphatidylinositol 3-Kinase in T Cells. Proc Natl Acad Sci U S A. 90, 7366-7370.
29. Pleiman, C. M., Hertz, W. M., and Cambier, J. C. (1994) Activation of Phosphatidylinositol-3' Kinase by Src-Family Kinase SH3 Binding to the p85 Subunit. Science. 263, 1609-1612.
30. Heasman, S. J., and Ridley, A. J. (2008) Mammalian Rho GTPases: New Insights into their Functions from in Vivo Studies. Nat Rev Mol Cell Biol. 9, 690-701.
31. Bokoch, G. M., Vlahos, C. J., Wang, Y., Knaus, U. G., and Traynor-Kaplan, A. E. (1996) Rac GTPase Interacts Specifically with Phosphatidylinositol 3-Kinase. Biochem J. 315 ( Pt 3), 775-779.
32. Zheng, Y., Bagrodia, S., and Cerione, R. A. (1994) Activation of Phosphoinositide 3-Kinase Activity by Cdc42Hs Binding to p85. J Biol Chem. 269, 18727-18730.
33. Chamberlain, M. D., Berry, T. R., Pastor, M. C., and Anderson, D. H. (2004) The p85alpha Subunit of Phosphatidylinositol 3'-Kinase Binds to and Stimulates the GTPase Activity of Rab Proteins. J Biol Chem. 279, 48607-48614.
34. Chamberlain, M. D., Oberg, J. C., Furber, L. A., Poland, S. F., Hawrysh, A. D., Knafelc, S. M., McBride, H. M., and Anderson, D. H. (2010) Deregulation of Rab5 and Rab4 Proteins in p85R274A-Expressing Cells Alters PDGFR Trafficking. Cell Signal. 22, 1562-1575.
35. Stenmark, H. (2009) Rab GTPases as Coordinators of Vesicle Traffic. Nat Rev Mol Cell Biol. 10, 513-525.
36. Chagpar, R. B., Links, P. H., Pastor, M. C., Furber, L. A., Hawrysh, A. D., Chamberlain, M. D., and Anderson, D. H. (2010) Direct Positive Regulation of PTEN by the p85 Subunit of Phosphatidylinositol 3-Kinase. Proc Natl Acad Sci U S A. 107, 5471-5476.
37. Dhand, R., Hiles, I., Panayotou, G., Roche, S., Fry, M. J., Gout, I., Totty, N. F., Truong, O., Vicendo, P., and Yonezawa, K. (1994) PI 3-Kinase is a Dual Specificity Enzyme: Autoregulation by an Intrinsic Protein-Serine Kinase Activity. EMBO J. 13, 522-533.
38. De Gregorio, G., Coppa, A., Cosentino, C., Ucci, S., Messina, S., Nicolussi, A., D'Inzeo, S., Di Pardo, A., Avvedimento, E. V., and Porcellini, A. (2007) The p85 Regulatory Subunit of PI3K Mediates TSH-cAMP-PKA Growth and Survival Signals. Oncogene. 26, 2039-2047.
39. Cuevas, B. D., Lu, Y., Mao, M., Zhang, J., LaPushin, R., Siminovitch, K., and Mills, G. B. (2001) Tyrosine Phosphorylation of p85 Relieves its Inhibitory Activity on Phosphatidylinositol 3-Kinase. J Biol Chem. 276, 27455-27461.
40. von Willebrand, M., Williams, S., Saxena, M., Gilman, J., Tailor, P., Jascur, T., Amarante-Mendes, G. P., Green, D. R., and Mustelin, T. (1998) Modification of Phosphatidylinositol 3-Kinase SH2 Domain Binding Properties by Abl- Or Lck-Mediated Tyrosine Phosphorylation at Tyr-688. J Biol Chem. 273, 3994-4000.
41. Kavanaugh, W. M., Turck, C. W., Klippel, A., and Williams, L. T. (1994) Tyrosine 508 of the 85-Kilodalton Subunit of Phosphatidylinositol 3-Kinase is Phosphorylated by the Platelet-Derived Growth Factor Receptor. Biochemistry. 33, 11046-11050.
42. Tsuboi, N., Utsunomiya, T., Roberts, R. L., Ito, H., Takahashi, K., Noda, M., and Takahashi, T. (2008) The Tyrosine Phosphatase CD148 Interacts with the p85 Regulatory Subunit of Phosphoinositide 3-Kinase. Biochem J. 413, 193-200.
43. Fang, D., and Liu, Y. C. (2001) Proteolysis-Independent Regulation of PI3K by Cbl-b-Mediated Ubiquitination in T Cells. Nat Immunol. 2, 870-875.
44. Rommel, C., Camps, M., and Ji, H. (2007) PI3K Delta and PI3K Gamma: Partners in Crime in Inflammation in Rheumatoid Arthritis and Beyond? Nat Rev Immunol. 7, 191-201.
45. Vanhaesebroeck, B., Welham, M. J., Kotani, K., Stein, R., Warne, P. H., Zvelebil, M. J., Higashi, K., Volinia, S., Downward, J., and Waterfield, M. D. (1997) P110delta, a Novel Phosphoinositide 3-Kinase in Leukocytes. Proc Natl Acad Sci U S A. 94, 4330-4335.
46. Beer-Hammer, S., Zebedin, E., von Holleben, M., Alferink, J., Reis, B., Dresing, P., Degrandi, D., Scheu, S., Hirsch, E., Sexl, V., Pfeffer, K., Nurnberg, B., and Piekorz, R. P. (2010) The Catalytic PI3K Isoforms p110gamma and p110delta Contribute to B Cell Development and Maintenance, Transformation, and Proliferation. J Leukoc Biol. 87, 1083-1095.
47. Okkenhaug, K., Bilancio, A., Emery, J. L., and Vanhaesebroeck, B. (2004) Phosphoinositide 3-Kinase in T Cell Activation and Survival. Biochem Soc Trans. 32, 332-335.
48. Deau, M. C., Heurtier, L., Frange, P., Suarez, F., Bole-Feysot, C., Nitschke, P., Cavazzana, M., Picard, C., Durandy, A., Fischer, A., and Kracker, S. (2015) A Human Immunodeficiency Caused by Mutations in the PIK3R1 Gene. J Clin Invest. 125, 1764-1765.
49. Conley, M. E., Dobbs, A. K., Quintana, A. M., Bosompem, A., Wang, Y. D., Coustan-Smith, E., Smith, A. M., Perez, E. E., and Murray, P. J. (2012) Agammaglobulinemia and Absent B Lineage Cells in a Patient Lacking the p85alpha Subunit of PI3K. J Exp Med. 209, 463-470.
50. Chudasama, K. K., Winnay, J., Johansson, S., Claudi, T., Konig, R., Haldorsen, I., Johansson, B., Woo, J. R., Aarskog, D., Sagen, J. V., Kahn, C. R., Molven, A., and Njolstad, P. R. (2013) SHORT Syndrome with Partial Lipodystrophy due to Impaired Phosphatidylinositol 3 Kinase Signaling. Am J Hum Genet. 93, 150-157.
51. Dyment, D. A., Smith, A. C., Alcantara, D., Schwartzentruber, J. A., Basel-Vanagaite, L., Curry, C. J., Temple, I. K., Reardon, W., Mansour, S., Haq, M. R., Gilbert, R., Lehmann, O. J., Vanstone, M. R., Beaulieu, C. L., FORGE Canada Consortium, Majewski, J., Bulman, D. E., O'Driscoll, M., Boycott, K. M., and Innes, A. M. (2013) Mutations in PIK3R1 Cause SHORT Syndrome. Am J Hum Genet. 93, 158-166.
52. Cheung, L. W., Hennessy, B. T., Li, J., Yu, S., Myers, A. P., Djordjevic, B., Lu, Y., Stemke-Hale, K., Dyer, M. D., Zhang, F., Ju, Z., Cantley, L. C., Scherer, S. E., Liang, H., Lu, K. H., Broaddus, R. R., and Mills, G. B. (2011) High Frequency of PIK3R1 and PIK3R2 Mutations in Endometrial Cancer Elucidates a Novel Mechanism for Regulation of PTEN Protein Stability. Cancer Discov. 1, 170-185.
53. Fruman, D. A., Mauvais-Jarvis, F., Pollard, D. A., Yballe, C. M., Brazil, D., Bronson, R. T., Kahn, C. R., and Cantley, L. C. (2000) Hypoglycaemia, Liver Necrosis and Perinatal Death in Mice Lacking all Isoforms of Phosphoinositide 3-Kinase p85 Alpha. Nat Genet. 26, 379-382.
54. Fruman, D. A., Snapper, S. B., Yballe, C. M., Davidson, L., Yu, J. Y., Alt, F. W., and Cantley, L. C. (1999) Impaired B Cell Development and Proliferation in Absence of Phosphoinositide 3-Kinase p85alpha. Science. 283, 393-397.
55. Terauchi, Y., Tsuji, Y., Satoh, S., Minoura, H., Murakami, K., Okuno, A., Inukai, K., Asano, T., Kaburagi, Y., Ueki, K., Nakajima, H., Hanafusa, T., Matsuzawa, Y., Sekihara, H., Yin, Y., Barrett, J. C., Oda, H., Ishikawa, T., Akanuma, Y., Komuro, I., Suzuki, M., Yamamura, K., Kodama, T., Suzuki, H., Yamamura, K., Kodama, T., Suzuki, H., Koyasu, S., Aizawa, S., Tobe, K., Fukui, Y., Yazaki, Y., and Kadowaki, T. (1999) Increased Insulin Sensitivity and Hypoglycaemia in Mice Lacking the p85 Alpha Subunit of Phosphoinositide 3-Kinase. Nat Genet. 21, 230-235.
|Science Writers||Anne Murray|
|Illustrators||Peter Jurek, Katherine Timer|
|Authors||Jeff SoRelle, Tao Yue, Ming Zeng, Xue Zhong, Bruce Beutler|
|List |< first << previous [record 17 of 511] next >> last >||