Phosphatidylinositol 3-kinase regulatory subunit alpha
Also known as: GRB1, PIK3R1
Function
Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling. Modulates the cellular response to ER stress by promoting nuclear translocation of XBP1 isoform 2 in a ER stress- and/or insulin-dependent manner during metabolic overloading in the liver and hence plays a role in glucose tolerance improvement.
Classification
- Family (Pfam)
- PF16454 PI3K_P85_iSH2, PF00620 RhoGAP, PF00017 SH2
- InterPro
- ISH2_PIK3R1, PI3K_P85_iSH2, PI3K_p85alpha_SH3, PI3kinase_P85_cSH2, PI3kinase_P85_nSH2, Rho_GTPase_activation_prot, RhoGAP_dom, SH2, SH2_dom_sf, SH3-like_dom_sf, SH3_domain
- Functional cluster
- Mixed Regulatory & Membrane Proteins
Experimental structures · PDB · 102
- 1A0N NMR
- 1AZG NMR
- 1H9O X-ray 1.79A
- 1PBW X-ray 2.00A
- 1PHT X-ray 2.00A
- 1PIC NMR
- 1PKS NMR
- 1PKT NMR
- 2IUG X-ray 1.89A
- 2IUH X-ray 2.00A
- 2IUI X-ray 2.40A
- 2RD0 X-ray 3.05A
- … and 90 more
A predicted model is available from AlphaFold.
Gene Ontology · 62
- GO:0005911 cell-cell junction
- GO:0005801 cis-Golgi network
- GO:0005737 cytoplasm
- GO:0005829 cytosol
- GO:0016020 membrane
- GO:0005634 nucleus
- GO:1990578 perinuclear endoplasmic reticulum membrane
- GO:0048471 perinuclear region of cytoplasm
- GO:0005942 phosphatidylinositol 3-kinase complex
- GO:0005943 phosphatidylinositol 3-kinase complex, class IA
- GO:0005886 plasma membrane
- GO:0046935 1-phosphatidylinositol-3-kinase regulator activity
- GO:0140767 enzyme-substrate adaptor activity
- GO:0043125 ErbB-3 class receptor binding
- GO:0005096 GTPase activator activity
- GO:0043559 insulin binding
- GO:0005158 insulin receptor binding
- GO:0043560 insulin receptor substrate binding
- GO:0005159 insulin-like growth factor receptor binding
- GO:0019209 kinase activator activity
- GO:0005168 neurotrophin TRKA receptor binding
- GO:0141038 phosphatidylinositol 3-kinase activator activity
- GO:0043548 phosphatidylinositol 3-kinase binding
- GO:0035014 phosphatidylinositol 3-kinase regulator activity
- GO:0036312 phosphatidylinositol 3-kinase regulatory subunit binding
- GO:0052742 phosphatidylinositol kinase activity
- GO:0001784 phosphotyrosine residue binding
- GO:0046982 protein heterodimerization activity
- GO:0019903 protein phosphatase binding
- GO:0005068 transmembrane receptor protein tyrosine kinase adaptor activity
- GO:0030183 B cell differentiation
- GO:0032869 cellular response to insulin stimulus
- GO:0019221 cytokine-mediated signaling pathway
- GO:0060396 growth hormone receptor signaling pathway
- GO:0006955 immune response
- GO:0008286 insulin receptor signaling pathway
- GO:0048009 insulin-like growth factor receptor signaling pathway
- GO:0035655 interleukin-18-mediated signaling pathway
- GO:0001678 intracellular glucose homeostasis
- GO:0042267 natural killer cell mediated cytotoxicity
- GO:0043066 negative regulation of apoptotic process
- GO:0051497 negative regulation of stress fiber assembly
- GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction
- GO:0046854 phosphatidylinositol phosphate biosynthetic process
- GO:0046326 positive regulation of D-glucose import across plasma membrane
- GO:1900103 positive regulation of endoplasmic reticulum unfolded protein response
- GO:0051491 positive regulation of filopodium assembly
- GO:0120183 positive regulation of focal adhesion disassembly
- GO:0010592 positive regulation of lamellipodium assembly
- GO:0042307 positive regulation of protein import into nucleus
- GO:1903078 positive regulation of protein localization to plasma membrane
- GO:0033120 positive regulation of RNA splicing
- GO:0048661 positive regulation of smooth muscle cell proliferation
- GO:0045944 positive regulation of transcription by RNA polymerase II
- GO:0000209 protein polyubiquitination
- GO:0050821 protein stabilization
- GO:0015031 protein transport
- GO:0034143 regulation of toll-like receptor 4 signaling pathway
- GO:0034976 response to endoplasmic reticulum stress
- GO:0034446 substrate adhesion-dependent cell spreading
- GO:0030217 T cell differentiation
- GO:0061470 T follicular helper cell differentiation
Disease associations
- SHORT syndrome MONDO:0010026
- agammaglobulinemia 7, autosomal recessive MONDO:0014083
- immunodeficiency 36 with lymphoproliferation MONDO:0014453
Drugs targeting this protein · 23
- PF-04691502 inhibitor
- OMIPALISIB inhibitor
- IZORLISIB inhibitor
- DACTOLISIB inhibitor
- APITOLISIB inhibitor
- BUPARLISIB inhibitor
- AZD-6482 inhibitor
- RECILISIB inhibitor
- SF-1126 inhibitor
- TASELISIB inhibitor
- PILARALISIB inhibitor
- VS-5584 inhibitor
- GSK-1059615 inhibitor
- BGT-226 inhibitor
- VOXTALISIB inhibitor
- PAXALISIB inhibitor
- SONOLISIB inhibitor
- SAMOTOLISIB inhibitor
- PUQUITINIB MESYLATE DIHYDRATE inhibitor
- PANULISIB inhibitor
- PICTILISIB inhibitor
- ZSTK-474 inhibitor
- GEDATOLISIB inhibitor
Related proteins · sequence + function similarity
- Phosphatidylinositol 3-kinase regulatory subunit alpha 1.00
- Phosphatidylinositol 3-kinase regulatory subunit alpha 0.99
- Phosphatidylinositol 3-kinase regulatory subunit alpha 0.99
- Phosphatidylinositol 3-kinase regulatory subunit alpha 0.99
- Phosphatidylinositol 3-kinase regulatory subunit alpha 0.93
- Phosphatidylinositol 3-kinase regulatory subunit gamma 0.79
- Phosphatidylinositol 3-kinase regulatory subunit gamma 0.79
- Phosphatidylinositol 3-kinase regulatory subunit gamma 0.78
- Phosphatidylinositol 3-kinase regulatory subunit gamma 0.75
- Rho GTPase-activating protein 26 0.68
- Oligophrenin-1 0.67
- Oligophrenin-1 0.67
Co-cited proteins · studied together in the literature
- Tegument protein UL46 homolog 1 shared papers
- Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform 4 shared papers
- T-cell receptor-associated transmembrane adapter 1 1 shared papers
- Phosphatidylinositol 3-kinase regulatory subunit alpha 2 shared papers
- Tyrosine-protein kinase Fgr 1 shared papers
- E3 ubiquitin-protein ligase CBL-B 3 shared papers
- Inducible T-cell costimulator 1 shared papers
- Tegument protein UL46 1 shared papers
- Genome polyprotein 1 shared papers
- Growth factor receptor-bound protein 2 12 shared papers
- 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 8 shared papers
- Polyunsaturated fatty acid 5-lipoxygenase 1 shared papers
Literature · 74 cited papers
- PI3K activation is enhanced by FOXM1D binding to p110 and p85 subunits. Signal Transduct. Target. Ther. · 2020
- Transmembrane domain-mediated Lck association underlies bystander and costimulatory ICOS signaling. Cell. Mol. Immunol. · 2020
- C1-Ten is a PTPase of nephrin, regulating podocyte hypertrophy through mTORC1 activation. Sci. Rep. · 2017
- Cancer/testis antigen PIWIL2 suppresses circadian rhythms by regulating the stability and activity of BMAL1 and CLOCK. Oncotarget · 2017
- Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice. Proc. Natl. Acad. Sci. U.S.A. · 2016
- Caspase-8 tyrosine-380 phosphorylation inhibits CD95 DISC function by preventing procaspase-8 maturation and cycling within the complex. Oncogene · 2016
- N-terminome analysis of the human mitochondrial proteome. Proteomics · 2015
- A human immunodeficiency caused by mutations in the PIK3R1 gene. J. Clin. Invest. · 2014
- Mutations in PIK3R1 cause SHORT syndrome. Am. J. Hum. Genet. · 2013
- SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. Am. J. Hum. Genet. · 2013
- PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy. Am. J. Hum. Genet. · 2013
- FAM83B-mediated activation of PI3K/AKT and MAPK signaling cooperates to promote epithelial cell transformation and resistance to targeted therapies. Oncotarget · 2013
- … and 62 more in the literature graph
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