Database for Annotation, Visualization and Integrated Discovery 2.1
National Institute of Allergy and Infectious Disease
The Database for Annotation, Visualization and Integrated Discovery
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phosphoinositide-3-kinase regulatory subunit 1(PIK3R1) phosphoinositide-3-kinase regulatory subunit 1(PIK3R1) Related Genes Homo sapiens
CHROMOSOME 5,
CYTOBAND 5q13.1,
ENSEMBL_GENE_ID ENSG00000145675,
GENERIF_SUMMARY Thus, the Met-326Ile variant of p85alpha is functional for intracellular signaling and adipocyte differentiation but has small alterations in protein expression and activity that could play a role in modifying insulin action., Expression of a mutated in a Hodgkin's lymphoma-derived cell line; the first detection in human hematopoietic cells further underlining a potential role of PI3-kinase/Akt signaling in human leukemogenesis, The p85 subunit of PI 3-kinase mediates GPIb-related activation signals and activates Src independently of the enzymatic activity of PI 3- kinase., Gene expression of full-length p85alpha is increased in skeletal muscle from type 2 diabetics, this is not reflected by increased protein. Defects in PI 3-kinase activity are likely due to impaired activation of the enzyme., The isoleucine variant of codon 326 of the p85alpha subunit of PI3-K might be associated with decreased risk of Prostate Cancer., p55gamma binds to Rb and modification of this association can lead to cell cycle arrest, protein whose expression is deregulated in the epidermis of the elderly., the role of p85-ALPHA in the survival of cancer cells that express wild-type PTEN, a triple complex between AR, p85alpha, and Src is required for androgen-stimulated PI3K/Akt activation, PI3K has a novel role as a bikunin target gene on uPA up-regulation and invasion, These findings reveal key events of the phosphatidylinositol 3-kinase pathway that play distinct roles to maintain tissue polarity and that when disrupted are instrumental in the malignant breast tumor phenotype., coupling of Gab1 to PI3K is important for biological responses in RET-expressing cells, Data suggest that SLP-76 may play a role in signaling pathways by interacting with the p85 subunit of phosphoinositide 3-kinase (PI3K)., p110gamma and p85alpha class Ia phosphoinositide 3-kinase (PI3K) subunits play roles in generating the antiapoptotic and chemoresistant phenotype associated with accelerated local tumor recurrence, PI3K regulates cell cycle progression and cell proliferation in human gastric tumor cells via Rb-mediated pathway; effect mediated through direct association with Rb via N-terminal end of its p55 kDa regulatory subunits and modulating Rb-E2F interactions, WAVE3-mediated migration in MDA-MB-231 cells via lamellipodia formation is activated downstream of PI3K and induced by PDGF, calcium activates PLC-gamma1 via increased PIP3 formation mediated by c-src- and fyn-activated PI3K, the nSH2 domain of the p85 regulatory subumit is responsible for p110 regulatory contacts, and its disruption leads to constitutive p110 activity, Inhibitors may provide an alternative route to effective PI3K pathway inhibition for breast cancer treatment., the signals induced by integrin alpha6beta1 modulate at the level of PI3K and Cdc42 activity to allow platelets to actively form filopodia, CD21 activation triggered Cbl tyrosine phosphorylation, which interacts with SH2 domains of p85 subunit, SH2 domains of Crk-L and with tyrosine phosphorylated Syk kinase. CD21 activation triggers dissociation of Cbl-Vav complex., SHP-2 recruitment to p85 is required for IGF-I-stimulated association of the p85/p110 complex with insulin receptor substrate-1 and for the subsequent activation of the PI-3 kinase pathway leading to increased cell migration, the PI3-K pathway negatively regulates TGF-beta/Smad signaling in neuroblastoma cells, increased expression of p85alpha may be one of the earliest molecular alterations in the mechanism of the insulin resistance associated with overfeeding, MyD88 bridges TLR5 engagement to PI3K activation in response to flagellin, Gab1 thus appears as a primary actor in coupling VEGFR-2 to PI3K/Akt, recruited through an amplification loop involving PtdIns(3,4,5)P3 and its PH domain, Hsp90 inhibition transiently activates Src kinase and promotes Src-dependent p85 PI3K and Akt and Erk activation, direct interactions between native Syk and PI3K proteins are differentially regulated during FcgammaR phagocytosis and endocytosis., It has recently been shown that Akt activation is associated with a worse outcome among endocrine treated breast cancer patients and that it also inhibits the progesterone receptor (PR) expression via the PI3K/Akt pathway in breast cancer cells., autotaxin induces uPA expression via the Gi-PI3K-Akt-NF-kappaB signaling pathway that might be critical for autotaxin-induced tumor cell invasion and metastasis, Association of single nucleotide polymorphisms with serum leptin and body fat may reflect a diminished ability of this enzyme to signal in ersponse to leptin., constitutively active Stat5 mutant forms a complex with the p85 subunit of phosphatidylinositol 3-kinase and the scaffolding adapter Gab2 in leukemic bone marrow cells, resulting in the activation of Akt/PKB, a crucial downstream target of PI3-K, hypothesized that variants in the SHP-2 gene PTPN11 and PI3K p85alpha subunit gene PIK3R1 may influence fasting levels of plasma apoB and/or LDL cholesterol, the WASp/SNX9/p85/CD28 complex enables a unique interface of endocytic, actin polymerizing, and signal transduction pathways required for CD28-mediated T cell costimulation, the recruitment of PI3K to the E-cadherin/beta-catenin/p120-catenin complex via beta-catenin at the plasma membrane is required for calcium-induced phospholipase C-gamma1 activation and, ultimately, keratinocyte differentiation, PI3K is not overexpressed in melanocytic lesions., These results indicate that the phosphatidylinositol 3-kinase/Akt/FoxO1 pathway participates in Ang II suppression of hSR-BI/CLA-1 expression and suggests that the endothelial receptor for hSR-BI/CLA-1 is downregulated by the renin-angiotensin system., These results support a model in which phagosomal PI3K generates PI(3,4,5)P(3) necessary for later stages of phagocytosis, PTEN determines whether those late stages can occur, and SHIP-1 regulates when and where they occur., PKC alpha may be associated with regulation of cell proliferation/migration/invasion in human poorly differentiated hepatocellular carcinoma cells, RhoG protects cells from apoptosis caused by the loss of anchorage through a PI3K-dependent mechanism, independent of its activation of Rac1, IGF-1 activates the IGF receptor/IRS/PI3K/PKB pathway, and that PI3Kalpha is essential for the potentiatory effect of IGF-1 on platelet responses, Endothelial cell PI 3-kinase activity and F-actin remodeling are required during lymphocyte diapedesis and identify a PI 3-kinase-dependent step following initial separation of the VE-cadherin barrier., study reports a 3.0 angstrom resolution structure of a complex between p110alpha and a polypeptide containing the p110alpha-binding domains of p85alpha; results suggest specific mechanisms for the effect of oncogenic mutations in p110alpha and p85alpha, PI3K is activated by toll-like receptor stimulation in primary human plasmacytoid predendritic cells (pDCs), and it is required for type I IFN production by pDCs, both at the transcriptional and protein levels, Binding of CD95 Ligand to CD95 on glioblastoma cells recruit Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-beta pathway and subsequent expression of matrix metalloproteinases., p85alpha and p110beta are essential for androgen-stimulated AR transactivation, and their aberrant expression or activation might play an important role in prostate cancer progression, structure of the complex between the catalytic subunit of PI3Kalpha, p110alpha, & a portion of its regulatory subunit, p85alpha reveals the majority of the oncogenic mutations occur at the interfaces between p110 domains & between p110 & p85 domains, the influenza A virus NS1 protein interacts with the p85beta, but not the p85alpha, subunit of phosphatidylinositol 3-kinase, caspase 8 has a role as a modulator of p85alpha Rab5-GAP activity and endosomal trafficking, ARF1 regulates epidermal growth factor-dependent breast cancer cell growth and invasion during cancer progression by controlling the activation of the phosphatidylinositol 3-kinase pathway, The PI3-kinase gene Met326Ile polymorphism may not be a major determinant for the development of polycystic ovary syndrome (PCOS), but it may modulate the concentrations of serum 17-OHP or free testosterone in PCOS patients., FGFR3 and p85 proteins interact in myeloma cells which express p85alpha and p85beta., Abnormal PI3K p85alpha expression occurs in the progression of colorectal cancer in close relation to the clinical stage., p85alpha and p85beta may recruit proteins in the endocytic machinery on Epo stimulation; mutated EpoRs from primary familial and congenital polycythemia patients lacking the 3 important tyrosines do not bind p85 or internalize on stimulation, an interaction between the regulatory subunit of PI3K, p85, and the adaptor protein CrkL is required for efficient NKG2D-mediated cellular cytotoxicity, CoA synthase is involved in signaling events in the cell and forms a functional complex with p85alphaPI3K in vivo., the PIK3R1 mutation is rare in human cancers, PTEN-p85 association involves the unphosphorylated form of PTEN engaged within the PTEN-associated complex and also includes the p110beta isoform of PI3K., Our results demonstrated that shRNA targeting COX-2, Akt1 and PIK3R1 downregulates their expression significantly in a sequence-specific manner, exerting proliferation and invasion inhibition effects on SGC7901 and U251 cells, Findings indicate a novel mechanism by which hypoxia induces CD36 expression via activation of HIF-1 and the phosphatidylinositol 3-kinase pathway., Data show that mesothelin is a potential target in reducing resistance to cytotoxic drugs, and mesothelin-treated cells revealed rapid tyrosine phosphorylation of the p85 subunit of PI3K., PI3K p85alpha depletion induces cell cycle arrest and apoptosis in colorectal cancer cells, findings show presence of frequent mutations in p85alpha in colon cancer, a majority of which occurs in the inter-Src homology-2 domain; these mutations uncouple & retain p85alpha's p110-stabilizing activity, while abrogating its p110-inhibitory activity, p85alpha regulatory protein binds directly to and enhances PTEN lipid phosphatase activity, PI3Kp85alpha gene silencing can significantly promote 5-fluorouracil-induced apoptosis of colorectal LoVo cells., Results substantiate the concept that the p85 subunit of PI3K has a tumor-suppressive role in the liver and possibly other tissues., Data show that the mutations weaken an inhibitory interaction between p85alpha and p110alpha., PI-3K p85 in gestational diabetes mellitus patients may be involved in the insulin signaling pathway, resulting in insulin resistance., PIK3R1 might play a role in the pathogenesis of hypersplenism due to portal hypertension, and inhibition of PIK3R1 expression might be a novel therapeutic strategy for it., In the current study, we have shown that p85alpha, the regulatory subunit of phosphatidylinositol-3-kinase, has a critical role in mediating p53 acetylation and promoter-specific transactivation in the ultraviolet B (UVB) response., Leukemia cells can regulate the expression of p85alpha by posttranscriptional regulation., rs3756668 located in 3'-UTR of the PIK3R1 gene is associated with insulin resistant phenotype, SIRT1 interacts in an insulin-independent manner with the PI3K adapter subunit p85, lipid kinase p110beta/p85beta elucidates an unusual SH2-domain-mediated inhibitory mechanism, Single nucleotide polymorphisms in PIK3R1 is associated with prostate cancer., found that PIK3R1 was somatically mutated in 43% of endometrial cancers and 12% of nonendometrioid endometrial cancers, We did not find any mutation in the GNAQ, AKT3, and PIK3R1 genes in various types of thyroid cancer., presence of TSC2 mutations, in addition to TSC1 mutations, underlines the involvement of mTOR signaling in urothelial carcinoma, This paper reports the first purification of a phosphoinositide 3-kinase and shows that the protein is a heterodimer of an 85 kd regulatory subunit that mediates binding to phosphorylated proteins and a 110 kd catalytic subunit., Data show that mutation of serine 83 to alanine on p85 inhibited 14-3-3zeta binding to the p85 subunit of PI3K., Multiple PIK3R1 and PIK3R2 mutations demonstrate gain of function, including disruption of a novel mechanism of pathway regulation wherein p85alpha dimers bind and stabilize PTEN., PIK3R1, like PIK3CA, is a potential therapeutic target in Glioblastoma multiforme and that it also influences tumor cell growth and motility, a global conformational change in p110alpha consistent with allosteric regulation of the kinase domain by the P85 N-terminal SH2 domain, Cyclin G1 overexpression enhanced Akt activation through interaction with p85 (regulatory subunit of phosphoinositide 3-kinase), High p85alpha is associated with non-small cell lung cancer., miR-376a may contribute to the development of hepatocellular carcinoma by targeting p85alpha, Insulin stimulation promoted an interaction between the IRS1/p85 complex and PPP1R12A; however, p85 and PPP1R12A did not interact independent of IRS1., Data indicate that erufosine caused dose-dependent decreases in the phosphorylation of PI3K (p85), Akt (PKB) at Thr 308 and cRaf in both MCF-7 and MDA-MB 231 cell lines., Introduction of a subset of the mutations identified in human glioblastoma, in the nSH2 and iSH2 domains, increases signaling through the PI3K pathway and promotes tumorigenesis of primary normal human astrocytes., Both alpha and beta isomers of the PI3K regulatory subunit p85 and full-length rotavirus NSP1 are important for this interaction, which results in efficient activation of the PI3K/Akt pathway during rotavirus infection., PI3K behaves as an upstream regulator of PKCdelta and p38 MAPK in WISH cells., Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells., Data indicate PI3K p85 mediates the interaction of beta-catenin with NF-kappaB (p65)., It is a key player in cell-growth signaling in a number of lymphoid malignancies., Individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling., A heterozygous PIK3R1 mutation is observed in two unrelated families affected by partial lipodystrophy, low body mass index, short stature, progeroid face, and Rieger anomaly (SHORT syndrome)., PIK3R1 mutations are the major cause of SHORT syndrome., miR-486 directly targets components of insulin growth factor (IGF) signaling including IGF1, IGF1 receptor, and phosphoinositide-3-kinase, regulatory subunit 1alpha (PIK3R1, or p85a) and functions as a potent tumor suppressor of lung cancer., PIK3R1 de novo missense mutation (c.1945C>T; p.Arg649Trp) cause SHORT syndrome., HSP20 directly associates with PI3K subunits and suppresses its activity in hepatocellular carcinoma, resulting in the inhibition of the AKT pathway, and subsequently decreasing the growth of hepatocellular carcinoma., PIK3CA mutations and PIK3R1 underexpression show opposite effects on patient outcome and could become useful prognostic and predictive factors in breast cancer., Knockdown of RPS7 resulted in increased expression of P85alpha, P110alpha, and AKT2., These data, plus the fact that Sam68 is known to be a signaling adaptor protein, indicated that Sam68 is a signal molecule with a functional role in the PI3K/Akt signal pathway during enterovirus 71 infection., mutant forms of p85alpha may play an oncogenic role in bladder cancer, MPP3 and Dlg, membrane-associated guanylate kinase homologs (MAGuK) proteins, connect CADM1 with p85 of PI3K by forming a multi-protein complex at the periphery of cells., High PI3K p85 expression is associated with non-small cell lung cancer., BRD7-mediated translocation of a subfraction (but not all) of the p85 protein to the nucleus could enhance PI3K signaling., SchA-FAK-p85 complex subsequently selectively recruited and activated Akt2, not Akt1, we report PIK3R1 as the gene implicated in SHORT syndrome in two patients., In trastuzumab-treated HER2-positive breast cancer patients, positive p85 protein expression appears to be a prognostic factor of poor survival and, if validated, might have important implications in the treatment of such patients., This study highlights the p85alpha (PI3K)S83 role as a key regulator of cell proliferation and motility induced by insulin in MCF-7 cells breast cancer model., PI3K activity is tightly regulated in T and B lymphocytes and that various defects in the PI3K-triggered pathway can cause primary immunodeficiencies., Data show that miR-221 and miR-222 repress respectively the levels of PIK3R1 and ETS1 to regulate angiogenic features in endothelial progenitor cells and endothelial cells., This study identified that CGPs was found to significantly correlate with the differential expression and methylation of genes encoding phosphoinositide-3-kinase, regulatory subunit 1., describe two neomorphic PIK3R1 mutants prevalent in endometrial and colon cancer that induce transformation via activation of PI3K-independent pathways, these data demonstrate that Pyk2 is a critical regulator of PI3K function downstream of the TCR., Data conclude that miR-486-5p, which is frequently downregulated in HCC, inhibits HCC progression by targeting PIK3R1 and phosphatidylinositol 3-kinase-AKT activation., Patients who harbor a recently reported heterozygous splice site mutation in PIK3R1 suffer from recurrent sinopulmonary infections and lymphoproliferation., genetic association studies in populations in Ireland and Belgium, Defective podocyte insulin signaling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy., PIK3R1 negatively regulates the epithelial-mesenchymal transition and stem-like phenotype of renal cancer cells through the AKT/GSK3beta/CTNNB1 signaling pathway, expression determinant of gemcitabine sensitivity in pancreatic ductal adenocarcinoma, Heterozygous splice site mutations in PIK3R1 are associated with an immunological phenotype resembling hyper-IgM syndrome, and altered germinal center reaction with abnormal B cell peripheral maturation., we conclude that miR-128-3p, which is frequently downregulated in HCC, inhibits hepatocellular carcinoma (HCC). progression by regulating PIK3R1 and PI3K/AKT activation, and is a prognostic marker for HCC patients., The synaptic recruitment of lipid rafts is dependent on CD19-PI3K module and cytoskeleton remodeling molecules., Analysis of interdomain interactions of wild-type and mutants at the p110alpha-p85alpha interface with molecular dynamics simulations suggest that tumor-associated mutations weaken interactions between p110alpha and p85alpha by disrupting key stabilizing interactions., Three of these, PIK3R1, VEGFA, and ITGB1, are known to be associated with preeclampsia or preeclampsia-related biological processes, As a consequence, homodimeric but not monomeric p85alpha suppresses the phosphatidylinositol 3-kinase pathway by protecting PTEN from E3 ligase WWP2-mediated proteasomal degradation., NOS stimulation via PI3K, calpain proteases, and SIRT1-dependent deacetylation downstream from VEGFR2 activation contributes to these vasodilator responses., study provides new insight into the structure and assembly of the p85alpha homodimer and suggests that this protein is a highly dynamic molecule whose conformational flexibility allows it to transiently associate with multiple binding proteins., A Cytosolic Multiprotein Complex Containing p85alpha Is Required for beta-Catenin Activation in Colitis and Colitis-associated Cancer., PIK3R1 knockdown abrogated antimiR21-induced effect on breast cancer cells., PI3KR1 plays a crucial role in the development of germinal center follicular helper T cells and is not involved in the generation of normal follicular regulatory T cells, RAC1/RAC2 and SFK are proximal and essential for phosphatidylinositol 3-kinase (PI3K) activation in NK cell-mediated direct cytotoxicity against Cryptococcus neoformans.,
OMIM_DISEASE SHORT syndrome, Agammaglobulinemia 7, autosomal recessive, Immunodeficiency 36,
SP_COMMENT disease:Defects in PIK3R1 are a cause of severe insulin resistance., domain:The SH3 domain mediates the binding to CBLB, and to HIV-1 Nef., 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., PTM:Polyubiquitinated in T-cells by CBLB; which does not promote proteasomal degradation but impairs association with CD28 and CD3Z upon T-cell activation., similarity:Belongs to the PI3K p85 subunit family., similarity:Contains 1 Rho-GAP domain., similarity:Contains 1 SH3 domain., similarity:Contains 2 SH2 domains., subunit:Heterodimer of a p110 (catalytic) and a p85 (regulatory) subunits. Interacts with phosphorylated TOM1L1. Interacts with phosphorylated LIME1 upon TCR and/or BCR activation. Interacts with SOCS7. Interacts with RUFY3 (By similarity). Interacts with phosphorylated LAT, LAX1 and TRAT1 upon TCR activation. Interacts with CBLB. Interacts with HIV-1 Nef to activate the Nef associated p21-activated kinase (PAK). This interaction depends on the C-terminus of both proteins and leads to increased production of HIV. Interacts with HCV NS5A. The SH2 domains interact with the YTHM motif of phosphorylated INSR in vitro. Also interacts with tyrosine-phosphorylated IGF1R in vitro. Interacts with CD28 and CD3Z upon T-cell activation. Interacts with IRS1 and phosphorylated IRS4, as well as with NISCH and HCST., tissue specificity:Isoform 2 is expressed in skeletal muscle and brain, and at lower levels in kidney and cardiac muscle. Isoform 2 and isoform 4 are present in skeletal muscle (at protein level).,