Phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1)
The protein contains 724 amino acids for an estimated molecular weight of 83598 Da.
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 (PubMed:17626883, PubMed:19805105, PubMed:7518429). 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 (PubMed:20348923). (updated: Dec. 20, 2017)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology.
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Biological Process
Axon guidance
B cell differentiation
Blood coagulation
Cellular glucose homeostasis
Cellular response to insulin stimulus
Cellular response to UV
Cytokine-mediated signaling pathway
Epidermal growth factor receptor signaling pathway
ERBB2 signaling pathway
Extrinsic apoptotic signaling pathway via death domain receptors
Fc-epsilon receptor signaling pathway
Fc-gamma receptor signaling pathway involved in phagocytosis
Fibroblast growth factor receptor signaling pathway
G protein-coupled receptor signaling pathway
Growth hormone receptor signaling pathway
Innate immune response
Insulin receptor signaling pathway
Insulin-like growth factor receptor signaling pathway
Interleukin-7-mediated signaling pathway
Intrinsic apoptotic signaling pathway in response to DNA damage
Leukocyte migration
MAPK cascade
Negative regulation of apoptotic process
Negative regulation of cell-matrix adhesion
Negative regulation of osteoclast differentiation
Negative regulation of stress fiber assembly
Neurotrophin TRK receptor signaling pathway
NFAT protein import into nucleus
Obsolete positive regulation of glucose import in response to insulin stimulus
Obsolete positive regulation of transcription factor import into nucleus
Phosphatidylinositol 3-kinase signaling
Phosphatidylinositol biosynthetic process
Phosphatidylinositol phosphate biosynthetic process
Phosphatidylinositol-mediated signaling
Phospholipid metabolic process
Platelet activation
Positive regulation of cell migration
Positive regulation of endoplasmic reticulum unfolded protein response
Positive regulation of establishment of protein localization to plasma membrane
Positive regulation of filopodium assembly
Positive regulation of focal adhesion disassembly
Positive regulation of glucose import
Positive regulation of lamellipodium assembly
Positive regulation of phosphatidylinositol 3-kinase signaling
Positive regulation of protein import into nucleus
Positive regulation of protein kinase B signaling
Positive regulation of protein localization to plasma membrane
Positive regulation of RNA splicing
Positive regulation of transcription by RNA polymerase II
Positive regulation of tumor necrosis factor production
Protein import into nucleus
Protein phosphorylation
Protein stabilization
Regulation of insulin receptor signaling pathway
Regulation of phosphatidylinositol 3-kinase activity
Regulation of stress fiber assembly
Response to endoplasmic reticulum stress
Small molecule metabolic process
Substrate adhesion-dependent cell spreading
T cell costimulation
T cell receptor signaling pathway
Vascular endothelial growth factor receptor signaling pathway
Viral process
Cellular Component
Cell-cell junction
Cis-Golgi network
Cytoplasm
Cytosol
Membrane
Nucleus
Obsolete cell
Perinuclear endoplasmic reticulum membrane
Perinuclear region of cytoplasm
Phosphatidylinositol 3-kinase complex
Phosphatidylinositol 3-kinase complex, class IA
Plasma membrane
Protein complex
Molecular Function
1-phosphatidylinositol-3-kinase activity
1-phosphatidylinositol-3-kinase regulator activity
ErbB-3 class receptor binding
Insulin binding
Insulin receptor binding
Insulin receptor substrate binding
Insulin-like growth factor receptor binding
Neurotrophin TRKA receptor binding
Phosphatidylinositol 3-kinase binding
Phosphatidylinositol 3-kinase regulator activity
Phosphatidylinositol 3-kinase regulatory subunit binding
Phosphatidylinositol-4,5-bisphosphate 3-kinase activity
Phosphotyrosine residue binding
Protein heterodimerization activity
Protein phosphatase binding
Transcription factor binding
Transmembrane receptor protein tyrosine kinase adaptor activity
The reference OMIM entry for this protein is 171833
Phosphatidylinositol 3-kinase, regulatory subunit 1; pik3r1
Phosphatidylinositol 3-kinase-associated p85-alpha; grb1
Phosphatidylinositol 3-kinase, regulatory subunit, 85-kd, alpha
P85-alpha
DESCRIPTION
Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates the inositol ring of phosphatidylinositol and related compounds at the 3-prime position. The products of these reactions are thought to serve as second messengers in growth signaling pathways. The kinase itself is made up of a catalytic subunit of molecular mass 110 kD (p110; e.g., PIK3CA, 171834) and a regulatory subunit, often of molecular mass 85 kD (p85), such as PIK3R1 (summary by Hoyle et al., 1994).CLONING
Otsu et al. (1991) showed that the bovine PI3K p85 subunit consists of 2 closely related proteins, p85-alpha and p85-beta (PIK3R2; 603157). They cloned cDNAs encoding both p85 subunits, each of which is a 724-amino acid polypeptide. The 2 subunits shared 62% amino acid sequence identity across their entire length. Both sequences contained an N-terminal SH3 region, 2 SH2 regions, and a region of homology to the C-terminal region of BCR (151410). Functional expression studies showed that both p85 subunits lacked PI3-kinase activity, but both bound to tyrosine kinase receptors. Volinia et al. (1992) stated that human p85-alpha contains all the peptide sequence found in bovine p85-alpha. Skolnik et al. (1991) developed a novel method for expression cloning of receptor tyrosine kinase target proteins (called CORT for 'cloning of receptor targets') and illustrated the method by cloning cDNA for GRB1, the gene encoding phosphatidylinositol 3-kinase-associated p85-alpha. The PIK3R1 gene encodes 3 regulatory isoforms of PI3K: p85, p55, and p50. The 9 3-prime exons are shared by all 3 isoforms with 2 distinct promoters, and 2 exon 1 sequences upstream of these 9 exons control the production of p55 and p50 (summary by Conley et al., 2012). Conley et al. (2012) found variable expression of the 3 regulatory isoforms in hematopoietic cells: normal T cells expressed almost equal amounts of p85 and p50, and activated T cells also contained trace amounts of p55. In contrast, normal B cells contained p85, but no detectable p50 or p55; EBV-transformed B cells expressed low levels of p50 and p55. NK cells and neutrophils contained p85 and low levels of p50.GENE FUNCTION
Skolnik et al. (1991) showed that the product of the GRB1 gene associates with activated growth factor receptors. p85-alpha modulates the interaction between PI3 kinase and platelet-derived growth factor receptor. Simoncini et al. (2000) showed that the estrogen receptor isoform ER-alpha (133430) binds in a ligand-dependent manner to the p85-alpha regulatory subunit of PI3K. Stimulation with estrogen increases ER-alpha-associated PI3K activity, leading to the activation of protein kinase B/AKT (164730) and endothelial nitric oxide synthase (eNOS; 163729). Recruitment and activation of PI3K by ligand-bound ER-alpha are independent of gene transcription, do not involve phosphotyrosine adaptor molecules or src-homology domains of p85-alpha, and extend to other steroid hormone receptors. Mice treated with estrogen showed increased eNOS activity and decreased vascular leukocyte accumulation after ischemia and reperfusion injury. This vascular protective effect of estrogen was abolished in the presence of PI3K or eNOS inhibitors. Simoncini et al. (2000) concluded that their findings defined a physiologically important nonnuclear estrogen-signaling pathway involving the direct interaction of ER-alpha with PI3K. Niswender et al. (2001) demonstrated that systemic adminis ... More on the omim web site
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 171833 was added.
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed