Affinage

PIK3R1

Phosphatidylinositol 3-kinase regulatory subunit alpha · UniProt P27986

Length
724 aa
Mass
83.6 kDa
Annotated
2026-04-28
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIK3R1-encoded p85α is the principal regulatory subunit of class IA phosphoinositide 3-kinases, functioning as both a stabilizer and inhibitor of p110 catalytic subunits through multivalent contacts involving its nSH2, iSH2, and cSH2 domains; relief of this inhibition occurs via SH2 engagement with receptor phosphotyrosines, Src-mediated Tyr688 phosphorylation, PKA-mediated Ser83 phosphorylation, TRAF6-catalyzed Lys63-linked ubiquitination at Lys513/519, and SUMOylation-deficient states (PMID:1372092, PMID:11337495, PMID:17016431, PMID:28676490, PMID:26411363). Beyond its catalytic-subunit partnership, free p85α homodimerizes via SH3–proline-rich, BH–BH, and cSH2–cSH2 interfaces, and these dimers bind and stabilize unphosphorylated PTEN by protecting it from WWP2-mediated proteasomal degradation, thereby providing a PI3K-independent tumor-suppressive mechanism (PMID:26222500, PMID:26475863, PMID:21984976). The BH domain confers GAP activity toward Rab5, Rab4, Cdc42, and Rac1, linking p85α to receptor trafficking and cytoskeletal regulation, while insulin-induced dimer dissociation liberates monomers that chaperone XBP-1s into the nucleus for ER stress resolution (PMID:15377662, PMID:20348926, PMID:25754093). Germline PIK3R1 splice-site mutations that delete part of the iSH2 domain cause activated PI3Kδ syndrome (APDS2), a primary immunodeficiency correctable by PI3Kδ inhibition, and somatic gain-of-function mutations drive oncogenesis through loss of p110 inhibition or neomorphic JNK/MAPK scaffolding (PMID:25133428, PMID:28167755, PMID:25284480).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1992 High

    Establishing how PI3K is recruited to activated receptors resolved a central signaling question: the two SH2 domains of p85α directly and specifically bind autophosphorylated receptor tyrosine kinases in a kinase-activity-dependent manner.

    Evidence In vitro binding with bacterially expressed SH2 fusion proteins plus in vivo co-immunoprecipitation from growth-factor-stimulated cells

    PMID:1372092

    Open questions at the time
    • Relative contributions of nSH2 versus cSH2 to receptor selectivity not resolved
    • Whether SH2 engagement directly relieves p110 inhibition not yet tested
  2. 1998 High

    The discovery that p85α participates in p53-dependent apoptosis from oxidative stress independently of PI3K catalytic activity revealed the first PI3K-independent function of the regulatory subunit.

    Evidence Homologous recombination knockout of p85 combined with p53ER chimeric system and oxidative-stress apoptosis assays

    PMID:9490416

    Open questions at the time
    • Molecular mechanism linking p85α to p53-dependent death pathway undefined
    • Whether this function requires p85α dimerization or specific domains not determined
  3. 1999 High

    Demonstrating that p85α self-associates into homodimers via SH3–proline-rich and BH–BH contacts established that the free (non-p110-bound) pool of p85α has an organized oligomeric state with potential independent signaling functions.

    Evidence Native molecular mass determination, deletion/point mutant analysis, and competition binding experiments in vitro and in vivo

    PMID:10212202

    Open questions at the time
    • Functional consequences of dimerization not yet defined
    • Stoichiometry and affinity of dimer in living cells not measured
  4. 2001 High

    Identifying Src-mediated Tyr688 phosphorylation as an intramolecular switch that relieves p85α inhibition of p110 revealed a post-translational mechanism for PI3K activation independent of receptor binding, with SHP1 serving as the off-switch.

    Evidence Site-directed mutagenesis (Y688A, Y688D), in vitro PI3K assays, and Akt/NF-κB readouts in SHP1-deficient cells

    PMID:11337495

    Open questions at the time
    • Structural basis of the pY688–nSH2 intramolecular interaction not resolved
    • Physiological contexts where Src-mediated activation dominates not mapped
  5. 2004 High

    Showing that the p85α BH domain possesses intrinsic GAP activity toward Rab5, Rab4, Cdc42, and Rac1 expanded p85α function beyond PI3K regulation into direct control of membrane trafficking and cytoskeletal dynamics.

    Evidence In vitro GTPase assays with purified proteins, direct binding pulldowns, and BH-domain mutagenesis affecting PDGFR degradation kinetics

    PMID:15377662

    Open questions at the time
    • Structural basis of BH domain GAP activity not determined
    • Relative contributions of GAP versus adaptor functions of BH domain in vivo unresolved
  6. 2006 High

    PKA phosphorylation of p85α Ser83 was found to modulate PI3K interaction with Ras, estrogen receptor binding, and cell cycle control, establishing another post-translational regulatory layer on p85α.

    Evidence In vitro and in vivo phosphorylation assays, S83A/S83D mutagenesis, PI3K activity and cell cycle/survival readouts

    PMID:17016431

    Open questions at the time
    • Whether Ser83 phosphorylation alters p85α dimerization or PTEN binding not tested
    • In vivo relevance in specific tissues not established
  7. 2009 High

    Structural and functional dissection of cancer-associated iSH2 mutations revealed that the iSH2 domain harbors separable p110-stabilizing and p110-inhibitory activities, and that oncogenic mutations selectively disrupt the inhibitory contacts (including the C2–iSH2 interface) while preserving stabilization.

    Evidence NMR, site-directed mutagenesis, in vitro kinase assays, cellular transformation, and anchorage-independent growth assays

    PMID:19915146 PMID:19962665

    Open questions at the time
    • Full set of inhibitory contacts across all p110 isoforms not mapped
    • In vivo tumorigenesis kinetics of individual mutations not compared
  8. 2010 High

    The finding that insulin disrupts p85α homodimers to release monomers that chaperone XBP-1s into the nucleus connected PI3K regulatory subunit biology to the unfolded protein response and insulin-driven ER stress resolution.

    Evidence Co-immunoprecipitation of p85 with XBP-1s, nuclear fractionation, and in vivo overexpression rescue in ob/ob mouse liver

    PMID:20348926

    Open questions at the time
    • Domain on p85α that contacts XBP-1s not mapped
    • Whether dimerization disruption is sufficient or insulin signaling provides additional signals not resolved
  9. 2011 High

    HDX-MS studies established that both nSH2 and cSH2 domains contribute to p110 inhibition in an isoform-selective manner (cSH2 inhibits p110β/δ but not p110α), and that phosphopeptide engagement increases heterodimer affinity for PIP2 membranes, providing a unified activation model.

    Evidence Hydrogen-deuterium exchange mass spectrometry, in vitro kinase assays, and FRET membrane-binding assays

    PMID:21827948

    Open questions at the time
    • How membrane engagement feeds back to alter SH2 domain conformation not resolved
    • Whether different RTK phosphopeptides produce distinct conformational outcomes not tested
  10. 2011 High

    Demonstrating that p85α dimers bind and stabilize PTEN protein, and that gain-of-function PIK3R1 mutations found in endometrial cancer disrupt this interaction leading to PTEN loss, revealed a major PI3K-independent tumor-suppressive role for the free p85α pool.

    Evidence Functional analysis of multiple mutations, co-immunoprecipitation of p85α dimers with PTEN, PI3K pathway readouts across endometrial tumor panels

    PMID:21984976

    Open questions at the time
    • Atomic-resolution structure of the p85α-dimer–PTEN complex not available
    • Whether PTEN stabilization is a general or tissue-specific function not established
  11. 2013 High

    Discovery that Cbl ubiquitinates p85, enabling its interaction with epsin-1 to drive EpoR endocytosis, established a non-canonical adaptor function for p85α in receptor trafficking and linked it to polycythemia vera-like disorders.

    Evidence Co-immunoprecipitation, dominant-negative Cbl, epsin-1 UIM mutants, EpoR internalization assays

    PMID:24113870

    Open questions at the time
    • Specific ubiquitination sites on p85α mediating epsin-1 interaction not identified
    • Whether this mechanism extends to other cytokine receptors not tested
  12. 2013 High

    Identification of a PIK3R1 splice-site mutation causing exon-10 deletion established that loss of p85α inhibitory function on p110δ causes a human primary immunodeficiency (APDS2), correctable by PI3Kδ inhibition.

    Evidence Whole-exome sequencing, patient T cell AKT phosphorylation, and PI3Kδ inhibitor rescue

    PMID:25133428

    Open questions at the time
    • Long-term clinical outcomes of PI3Kδ inhibitor therapy not established
    • Whether compensatory upregulation of p85β modifies disease severity not explored
  13. 2014 High

    The finding that truncation mutations R348* and L370fs relocalize p85α to the nucleus where it scaffolds JNK/ERK signaling components revealed a neomorphic oncogenic mechanism entirely independent of PI3K catalytic activity.

    Evidence Subcellular localization, JNK/ERK pathway phosphorylation, MEK/JNK inhibitor sensitivity in vitro and in vivo

    PMID:25284480

    Open questions at the time
    • Direct binding partners of nuclear truncated p85α in the JNK/ERK pathway not fully mapped
    • Whether neomorphic signaling occurs in non-cancer contexts unknown
  14. 2015 High

    Detailed biochemical reconstitution showed that p85α homodimers protect unphosphorylated PTEN from WWP2-mediated degradation and enhance PTEN membrane association and lipid phosphatase activity, completing the mechanistic picture of p85α as a PTEN guardian.

    Evidence Homodimerization, PTEN binding, WWP2 ubiquitination/degradation, lipid phosphatase activity assays, cancer mutation validation

    PMID:26222500

    Open questions at the time
    • Whether p85α dimer–PTEN interaction is regulated by growth factor signaling not determined
    • Structural model of the trimeric p85α-dimer–PTEN complex lacking
  15. 2015 High

    Identification of SUMO1/SUMO2 conjugation at iSH2 lysines as a negative regulator of PI3K signaling added SUMOylation to the post-translational code governing p85α activity, with loss of SUMOylation increasing tyrosine phosphorylation, migration, and transformation.

    Evidence SUMO conjugation assays, SUMOylation-site mutagenesis, PI3K activation, migration, and transformation assays

    PMID:26411363

    Open questions at the time
    • Specific SUMO E3 ligase(s) responsible not identified
    • Whether SUMOylation affects p85α dimerization or PTEN binding not tested
  16. 2015 High

    Biophysical characterization using AUC, SAXS, and live-cell fluorescence fluctuation spectroscopy refined the p85α dimer model, revealing an additional cSH2–cSH2 contact and showing that dimerization is rapidly reversible and concentration-dependent in living cells.

    Evidence Analytical ultracentrifugation, small-angle X-ray scattering, chemical cross-linking/MS, fluorescence fluctuation spectroscopy

    PMID:26475863

    Open questions at the time
    • Full atomic-resolution structure of the dimer not available
    • Regulation of dimer equilibrium by post-translational modifications not systematically tested
  17. 2017 High

    TRAF6-catalyzed Lys63-linked ubiquitination of p85α at Lys513/519 was shown to promote TGF-β receptor–p85α complex formation and PI3K-AKT activation independently of TβRI kinase activity, revealing a ubiquitin-dependent activation mechanism.

    Evidence Co-IP, proximity ligation assay, K513R/K519R mutagenesis, cell migration, and prostate cancer tissue PLA

    PMID:28676490

    Open questions at the time
    • Deubiquitinase(s) that reverse this modification unknown
    • Structural impact of K63-ubiquitin chains on p85α–p110 inhibitory interface not determined
  18. 2017 High

    Quantitative HDX-MS comparison of APDS2 mutant p85α with wild-type demonstrated >300-fold selective activation of p110δ over p110α, explaining the immunodeficiency phenotype and confirming isoform-specific therapeutic targeting by idelalisib.

    Evidence Biochemical kinase assays and HDX-MS on wild-type versus APDS2-mutant p85α–p110 complexes

    PMID:28167755

    Open questions at the time
    • Whether other p85α mutations cause similarly isoform-selective activation not fully surveyed
    • In vivo pharmacodynamic validation in patient immune cells limited
  19. 2019 High

    PIK3R1 loss was shown to activate not only AKT via enhanced p110α activity and decreased PTEN, but also a p110-independent JAK2/STAT3 axis through deregulated Gab2 phosphorylation, establishing that p85α constrains parallel oncogenic pathways.

    Evidence PIK3R1 knockdown, phosphoproteomics, Gab2 co-IP, combination AKT/STAT3 inhibitor studies in vitro and in vivo

    PMID:30755611

    Open questions at the time
    • Direct physical interaction between p85α and JAK2 not demonstrated
    • Whether the Gab2-STAT3 axis is tissue-specific not tested
  20. 2023 High

    NLRP6 recruits RBX1 to ubiquitinate p85α at Lys256, targeting it for OPTN-mediated selective autophagy; this degradation reduces free p85α available to stabilize PTEN, activating PI3K/AKT, providing a mechanism linking inflammasome components to PI3K pathway control.

    Evidence Co-IP, K256R mutagenesis, ubiquitination assays, autophagic flux assays, OPTN pulldown, in vivo tumor growth

    PMID:37770465

    Open questions at the time
    • Whether NLRP6-mediated p85α degradation occurs outside tumor contexts not tested
    • Relationship between autophagic degradation and proteasomal ubiquitination routes for p85α not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive characterization of individual regulatory inputs, a unified structural model integrating p85α dimerization, PTEN binding, post-translational modifications, and p110 inhibition/activation remains unresolved.
  • Full-length p85α dimer structure at atomic resolution not available
  • Quantitative model of how competing post-translational modifications (SUMOylation, ubiquitination, phosphorylation) integrate to set PI3K output not established
  • In vivo stoichiometry of free p85α monomers, dimers, and p110-bound heterodimers across tissues not measured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7 GO:0060090 molecular adaptor activity 3 GO:0003924 GTPase activity 1
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 11 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9612973 Autophagy 1
Partners
BRD7CBLNLRP6PIK3CAPIK3CDPTENTRAF6XBP1
Complex memberships
PI3K (p85α/p110 heterodimer)PTEN-associated complex (PAC)p85α homodimer

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 The two SH2 domains of p85α directly bind to autophosphorylated growth factor receptors (PDGF receptor, CSF-1 receptor, Kit) in a receptor tyrosine kinase activity-dependent manner, establishing that p85α SH2 domains are primarily responsible for PI3K recruitment to activated receptors. Bacterially expressed SH2 domain fusion proteins used in in vitro binding assays and in vivo co-immunoprecipitation Molecular and cellular biology High 1372092
1999 p85α self-associates into homodimers via intermolecular SH3 domain–proline-rich motif interactions and BH–BH domain interactions, both in vitro and in vivo. Deletion and point mutant analysis, native molecular mass determination, competition experiments The Journal of biological chemistry High 10212202
2001 Src family kinase-mediated phosphorylation of Tyr688 on p85α relieves its inhibitory activity on the p110 catalytic subunit, acting via an intramolecular interaction between phosphorylated Tyr688 and the nSH2 domain; SHP1 reverses this phosphorylation. Mutation Y688D mimics phosphorylation and fully reverses p85α inhibition of Akt and NF-κB. In vitro PI3K activity assay, site-directed mutagenesis (Y688A, Y688D), Akt/NF-κB phosphorylation readouts, SHP1-deficient cells The Journal of biological chemistry High 11337495
2001 The cytoplasmic tail of ADAM 12 directly interacts with the SH3 domain of p85α via three PXXP motifs (residues 825–828, 833–836, 884–887), and this interaction recruits PI3K to the plasma membrane to activate it, as shown by GFP-PH domain translocation. In vitro binding, site-directed mutagenesis of PXXP motifs, GFP-PH domain translocation assay in C2C12 cells The Journal of biological chemistry High 11313349
2001 p85α adaptor function can activate NFAT transcription and cooperate with TcR/CD3 to enhance IL-2 transcription in T cells independently of p110 catalytic activity; this function requires the BH domain and correlates with Rac1 binding. Expression of p110-uncoupled Δp85, NFAT/IL-2 reporter assays, BH domain deletion analysis, Rac1 binding The Journal of biological chemistry Medium 11679587
2004 p85α directly binds Rab5 and Rab4 via its BH domain and stimulates their GTPase activity (GAP activity); it also has GAP activity toward Cdc42 and Rac1. BH domain mutants of p85α show reduced PDGFR degradation rates and sustained MAPK/Akt activation. In vitro GTPase assay with purified proteins, direct binding (pulldown), BH domain mutagenesis, receptor degradation assays The Journal of biological chemistry High 15377662
2006 Gαq directly inhibits p110α/p85α PI3K in a GTP-dependent manner by binding to the p85-binding domain of p110α and competing with Ras for binding to p110α/p85α, thereby inhibiting PI3K/Akt signaling. Purified protein binding, fluorescence spectroscopy affinity measurements, co-precipitation with deletion mutants, cell-based PI3K/Akt readout The Biochemical journal High 16268778
2006 PKA phosphorylates Ser83 on p85α in vivo and in vitro; this phosphorylation is required for cAMP-induced G1 arrest, protection from anoikis, PI3K binding to Ras, and amplification of estrogen receptor–p85α interaction. S83A and S83D mutations respectively block and mimic these effects. In vitro and in vivo phosphorylation, site-directed mutagenesis (S83A, S83D), PI3K activity assay, cell cycle and survival assays Oncogene High 17016431
2008 miR-29 family members directly suppress p85α (PIK3R1) and CDC42 mRNA, leading to increased p53 levels and p53-dependent apoptosis. miRNA screen, luciferase reporter assay, Western blot, apoptosis assay Nature structural & molecular biology High 19079265
2008 In brain, Axl receptor tyrosine kinase directly binds p85 at two pYXXM sites (pY779 and pY821), and p85 can also interact indirectly via the p85 proline-rich region–Grb2 SH3 domain; Grb2 and p85 compete for binding at pY821. This assembly recruits and activates PI3K and phosphorylates Akt. Pulldown assays, co-immunoprecipitation with wildtype and mutant Axl, Gas6 stimulation in COS7 cells, brain homogenate validation Journal of neurochemistry High 18346204
2009 Somatic mutations in p85α in the iSH2 domain uncouple its p110-stabilizing activity from its p110-inhibitory activity, resulting in constitutive PI3K pathway activation, AKT phosphorylation, and oncogenesis in a p110-dependent manner. Mutation analysis, in vitro p110 inhibition assays, Akt activation, anchorage-independent growth, tumorigenesis assays Cancer cell High 19962665
2009 C2 domain–iSH2 domain contacts (p110α-N345 and p85-D560/N564) are required for full p85-mediated inhibition of p110α; cancer-associated truncations and point mutations in p85 disrupt this interface to relieve inhibition. NMR tau_c measurements, site-directed mutagenesis, in vitro kinase assays, cellular transformation assays Proceedings of the National Academy of Sciences of the United States of America High 19915146
2009 p85α associates with the unphosphorylated form of PTEN within the PTEN-associated complex (PAC), which also includes p110β; this association is enhanced by trastuzumab and linked to decreased AKT phosphorylation. Co-immunoprecipitation with newly generated antibodies, fractionation to identify PAC, correlation with AKT activity in ERBB2-amplified breast cancer cells Molecular and cellular biology Medium 19635806
2010 p85α and p85β form homodimers that are disrupted by insulin; the resulting monomers interact with spliced XBP-1 (XBP-1s) and increase its nuclear translocation. In ob/ob mice, the p85–XBP-1s interaction is lost, causing defective ER stress resolution that is rescued by p85α/p85β overexpression. Co-immunoprecipitation, nuclear fractionation, in vivo overexpression in ob/ob mouse liver Nature medicine High 20348926
2011 Multiple PIK3R1 mutations demonstrate gain of function and disrupt a novel regulatory mechanism in which p85α dimers bind and stabilize PTEN protein; loss of this dimer-PTEN interaction leads to PTEN protein loss and PI3K pathway activation. Functional mutation analysis, co-immunoprecipitation of p85α dimers with PTEN, PI3K pathway activation readouts in endometrial cancer Cancer discovery High 21984976
2011 Both nSH2 and cSH2 domains of p85α contribute to inhibition of p110δ (cSH2 inhibits p110β and p110δ but not p110α); binding RTK phosphopeptides disengages SH2 domains and greatly increases heterodimer affinity for PIP2-containing membranes. Hydrogen-deuterium exchange mass spectrometry (DXMS), in vitro kinase assays, FRET membrane binding assay Structure High 21827948
2013 A heterozygous splice site mutation in PIK3R1 causing deletion of exon 10 produces a shortened p85α lacking part of the PI3K p110-binding domain, resulting in elevated AKT phosphorylation due to failure to inhibit p110 activity, and causing a primary immunodeficiency phenotype correctable by PI3Kδ inhibitor. Whole-exome sequencing, patient T cell AKT phosphorylation assays, PI3Kδ inhibitor rescue experiment The Journal of clinical investigation High 25133428
2014 BRD7 binds to the iSH2 domain of p85α via a conserved C-terminal region and facilitates nuclear translocation of p85α, depleting cytosolic p85α/p110 complexes and thereby decreasing p110 stability and PI3K pathway signaling. Co-immunoprecipitation, RNAi knockdown/overexpression, subcellular fractionation, Akt phosphorylation assays Molecular cell High 24657164
2014 The heterozygous PIK3R1 splice site mutation (skipping amino acids 434–475 of the iSH2 domain) causes dominant activation of PI3Kδ signaling due to qualitative and quantitative binding changes in the p85α–p110δ complex and failure of the C-terminal region to properly inhibit p110δ. Patient cell biochemical analysis, overexpression in healthy T cells, immunoprecipitation, kinase assays The Journal of experimental medicine High 25488983
2014 The common PIK3R1 truncation mutation R348* and the nearby L370fs localize to the nucleus and serve as scaffolds for JNK pathway components, unexpectedly activating JNK and ERK signaling (neomorphic function) independently of PI3K, conferring sensitivity to MEK and JNK inhibitors. In vitro and in vivo inhibitor sensitivity assays, subcellular localization studies, phosphorylation of JNK/ERK pathway components Cancer cell High 25284480
2015 p85α homodimerizes via SH3:proline-rich region and BH:BH intermolecular interactions to selectively bind unphosphorylated active PTEN, protecting PTEN from WWP2 E3 ligase-mediated proteasomal degradation and enhancing PTEN lipid phosphatase activity and membrane association. Cancer-associated mutations targeting the homodimerization or PTEN interaction surface disrupt these functions. Biochemical homodimerization assays, PTEN binding assays, ubiquitination/degradation assays, lipid phosphatase activity assay, cancer mutation analysis eLife High 26222500
2015 SUMO1 and SUMO2 are conjugated to p85α (and p85β) at lysine residues in the iSH2 domain; SUMOylation-defective mutants show higher PI3K pathway activation, increased cell migration and transformation. SUMO conjugation also reduces tyrosine phosphorylation of p85, and loss of SUMOylation increases tyrosine-phosphorylated p85 levels. SUMO conjugation assays, site-directed mutagenesis of SUMOylation sites, PI3K pathway activation readout, migration and transformation assays Oncogene High 26411363
2015 PIK3R1 mutations in the cSH2 domain (e.g., R649W) decrease sensitivity to activation by receptor tyrosine kinases; iSH2 truncation oncogenic mutations (Q572*) disrupt all p85-inhibitory inputs and cause differential hyper-activation of p110α vs p110δ, as revealed by HDX-MS. Hydrogen-deuterium exchange mass spectrometry, in vitro kinase assays with recombinant proteins Structure High 31831213
2017 TRAF6 polyubiquitylates p85α at Lys513 and Lys519 (Lys63-linked) in the iSH2 domain, promoting formation of a TGF-β type I receptor–p85α complex and activating PI3K-AKT signaling and cell motility independently of TβRI kinase activity. Co-immunoprecipitation, in situ proximity ligation assay, site-directed mutagenesis of ubiquitination sites (K513R/K519R), cell migration assays, prostate cancer tissue PLA Science signaling High 28676490
2017 APDS2 splice mutation in p85α (Δ434-475) leads to >300-fold basal activation of p110δ but only ~2-fold activation of p110α, by disrupting inhibitory contacts from nSH2, iSH2, and cSH2 domains; APDS1 mutations in p110δ mimic oncogenic p110α activation mechanisms. All APDS mutations are inhibited by idelalisib. Biochemical activity assays, hydrogen-deuterium exchange mass spectrometry Proceedings of the National Academy of Sciences of the United States of America High 28167755
2013 Cbl ubiquitinates the p85 regulatory subunit of PI3K; ubiquitinated p85 interacts with the endocytic protein epsin-1 (via ubiquitin-interacting motifs), driving EpoR endocytosis and terminating Epo signaling. EpoR mutants from PFCP patients cannot bind p85 and fail to internalize. Co-immunoprecipitation, dominant-negative Cbl expression, epsin-1 UIM mutant expression, EpoR internalization assays, erythroid progenitor Epo-sensitivity assays Blood High 24113870
2019 PIK3R1 loss activates AKT via enhanced p110α kinase activity and decreased PTEN, and also activates a p110-independent JAK2/STAT3 signaling pathway through deregulated Gab2 phosphorylation; combined AKT and STAT3 inhibition has enhanced anti-tumor effect compared to monotherapy. PIK3R1 knockdown, phosphoproteomics/co-immunoprecipitation of Gab2, pathway activation assays, combination drug treatment in vitro and in vivo Nature communications High 30755611
2023 NLRP6 binds p85α and recruits the E3 ligase RBX1 to ubiquitinate p85α at Lys256, which is then recognized by autophagy cargo receptor OPTN, causing selective autophagic degradation of p85α and subsequent PI3K/AKT pathway activation by reducing PTEN stability. Co-immunoprecipitation, site-directed mutagenesis (K256R), ubiquitination assay, autophagic flux assays, OPTN pulldown, in vitro and in vivo tumor growth assays Nature communications High 37770465
1998 p85 participates in p53-dependent apoptosis in response to oxidative stress independently of PI3K; p85 is upregulated by p53 and is required for oxidative stress-induced cell death, as demonstrated by p85 disruption through homologous recombination. Homologous recombination knockout, p53ER chimeric protein system, apoptosis assays under oxidative stress Nature High 9490416
2015 PIK3R1 loss-of-function via CRISPR/Cas9 promotes AKT phosphorylation, EMT, stem-like phenotype, and enhanced proliferation/migration in renal cancer cells through the AKT/GSK3β/CTNNB1 pathway; shRNA knockdown of AKT reduces p-GSK3β and CTNNB1, and CTNNB1 depletion impairs stem-like phenotype. CRISPR/Cas9 knockout, shRNA knockdown, AKT and CTNNB1 inhibition, EMT and stem-cell marker assays Scientific reports Medium 25757764
2015 p85α promotes nuclear translocation of XBP-1s downstream of podocyte insulin signaling; genetic ablation of PIK3R1 (p85α or p85β) in podocytes impairs XBP-1s nuclear translocation, activates ATF6/CHOP, and exacerbates diabetic nephropathy. Podocyte-specific genetic ablation, nuclear fractionation, XBP-1s translocation assay, in vivo DN model Nature communications High 25754093
2021 CBL mutations increase LYN kinase activation and interaction with mutant CBL, driving enhanced CBL phosphorylation, PIK3R1 (p85α) recruitment to CBL, and downstream PI3K/AKT signaling. LYN genetic ablation or dasatinib inhibition reduces CBL-PIK3R1 interaction and PI3K/AKT signaling. Global phosphoproteomics, CBL interactome mass spectrometry, genetic ablation of LYN, dasatinib inhibition, in vitro and in vivo anti-proliferative assays Blood High 33512474
2016 PIK3R1 C-terminal mutations severely reduce insulin-stimulated association of mutant p85α with IRS1 in patient cells. Mutant p85α overexpression in 3T3-L1 preadipocytes attenuates insulin-induced AKT phosphorylation and adipocyte differentiation, demonstrating context-dependent impairment of insulin signaling. Patient-derived cell co-immunoprecipitation (IRS1-p85α association), mutant p85α overexpression, AKT phosphorylation assay, adipocyte differentiation assay JCI insight High 27766312
2015 p85α deficiency in mesenchymal stem cells results in impaired osteoblast differentiation associated with increased Akt and MAPK activation; MAPK inhibitor (PD98059) but not PI3K inhibitor (LY294002) significantly restores osteoblast differentiation, placing p85α upstream of MAPK in this context. p85α knockout cells, osteoblast differentiation assays (ALP, osteocalcin), PI3K/MAPK inhibitors (LY294002, PD98059), genetic epistasis The Journal of biological chemistry Medium 21324896
2015 p85α assembly into homodimers is mediated by SH3:PR1 and an additional cSH2:cSH2 intermolecular interaction; p85α undergoes rapidly reversible, highly exothermic concentration-dependent monomer-dimer equilibrium both in vitro and in vivo (live-cell fluorescence fluctuation spectroscopy). Analytical ultracentrifugation, fluorescence fluctuation spectroscopy, small angle X-ray scattering, chemical cross-linking/mass spectrometry The Journal of biological chemistry High 26475863

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 miR-29 miRNAs activate p53 by targeting p85 alpha and CDC42. Nature structural & molecular biology 537 19079265
2011 High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer discovery 396 21984976
2019 Circular RNA AKT3 upregulates PIK3R1 to enhance cisplatin resistance in gastric cancer via miR-198 suppression. Molecular cancer 336 30927924
2009 Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation. Cancer cell 260 19962665
2010 The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation. Nature medicine 244 20348926
2014 Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. The Journal of experimental medicine 233 25488983
2001 Tyrosine phosphorylation of p85 relieves its inhibitory activity on phosphatidylinositol 3-kinase. The Journal of biological chemistry 217 11337495
1994 Activation of p70/p85 S6 kinase by a pathway independent of p21ras. Nature 212 8090223
2014 A human immunodeficiency caused by mutations in the PIK3R1 gene. The Journal of clinical investigation 204 25133428
1992 SH2 domains of the p85 alpha subunit of phosphatidylinositol 3-kinase regulate binding to growth factor receptors. Molecular and cellular biology 191 1372092
2017 TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α. Science signaling 184 28676490
2015 Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy. Nature communications 155 25754093
2020 circNFIB1 inhibits lymphangiogenesis and lymphatic metastasis via the miR-486-5p/PIK3R1/VEGF-C axis in pancreatic cancer. Molecular cancer 150 32366257
1998 Involvement of p85 in p53-dependent apoptotic response to oxidative stress. Nature 150 9490416
2013 Mutations in PIK3R1 cause SHORT syndrome. American journal of human genetics 147 23810382
2018 microRNA-155 positively regulates glucose metabolism via PIK3R1-FOXO3a-cMYC axis in breast cancer. Oncogene 124 29527004
2007 CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer. Blood 124 18006698
2018 Characterization of PIK3CA and PIK3R1 somatic mutations in Chinese breast cancer patients. Nature communications 122 29636477
2019 The Opposing Roles of PIK3R1/p85α and PIK3R2/p85β in Cancer. Trends in cancer 112 30961830
2017 Aberrant low expression of p85α in stromal fibroblasts promotes breast cancer cell metastasis through exosome-mediated paracrine Wnt10b. Oncogene 105 28394344
2017 Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in PIK3CD and PIK3R1. Proceedings of the National Academy of Sciences of the United States of America 97 28167755
2011 Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells. Oncotarget 97 22064833
2004 The p85alpha subunit of phosphatidylinositol 3'-kinase binds to and stimulates the GTPase activity of Rab proteins. The Journal of biological chemistry 95 15377662
2014 MicroRNA-486-5p, which is downregulated in hepatocellular carcinoma, suppresses tumor growth by targeting PIK3R1. The FEBS journal 87 25475121
2011 Dynamics of the phosphoinositide 3-kinase p110δ interaction with p85α and membranes reveals aspects of regulation distinct from p110α. Structure (London, England : 1993) 86 21827948
2022 Pan-cancer analysis on the role of PIK3R1 and PIK3R2 in human tumors. Scientific reports 81 35395865
2009 p85 Associates with unphosphorylated PTEN and the PTEN-associated complex. Molecular and cellular biology 80 19635806
2009 Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110alpha and are disrupted in oncogenic p85 mutants. Proceedings of the National Academy of Sciences of the United States of America 80 19915146
2014 Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors. Cancer cell 79 25284480
2014 BRD7, a tumor suppressor, interacts with p85α and regulates PI3K activity. Molecular cell 75 24657164
2015 Regulation of the PI3K pathway through a p85α monomer-homodimer equilibrium. eLife 73 26222500
2023 The Role of PIK3R1 in Metabolic Function and Insulin Sensitivity. International journal of molecular sciences 70 37628845
2015 Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management. Clinical genetics 69 26497935
2008 Insights into the oncogenic effects of PIK3CA mutations from the structure of p110alpha/p85alpha. Cell cycle (Georgetown, Tex.) 65 18418043
2006 p85 regulatory subunit of PI3K mediates cAMP-PKA and estrogens biological effects on growth and survival. Oncogene 62 17016431
2015 PIK3R1 negatively regulates the epithelial-mesenchymal transition and stem-like phenotype of renal cancer cells through the AKT/GSK3β/CTNNB1 signaling pathway. Scientific reports 61 25757764
1998 Differential activation of p70 and p85 S6 kinase isoforms during cardiac hypertrophy in the adult mammal. The Journal of biological chemistry 59 9733756
2005 p85alpha subunit of class IA PI-3 kinase is crucial for macrophage growth and migration. Blood 56 15769893
2016 Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations. JCI insight 55 27766312
2020 Glyphosate induces lymphocyte cell dysfunction and apoptosis via regulation of miR-203 targeting of PIK3R1 in common carp (Cyprinus carpio L.). Fish & shellfish immunology 54 32217141
2007 The IREM-1 (CD300f) inhibitory receptor associates with the p85alpha subunit of phosphoinositide 3-kinase. Journal of immunology (Baltimore, Md. : 1950) 53 17202342
2016 Targeting therapeutic liabilities engendered by PIK3R1 mutations for cancer treatment. Pharmacogenomics 51 26807692
2012 Attenuated Pik3r1 expression prevents insulin resistance and adipose tissue macrophage accumulation in diet-induced obese mice. Diabetes 49 22698915
2012 Somatic mutations of PIK3R1 promote gliomagenesis. PloS one 49 23166678
2019 CapG promotes resistance to paclitaxel in breast cancer through transactivation of PIK3R1/P50. Theranostics 48 31660072
2017 FOXA1 inhibits hepatocellular carcinoma progression by suppressing PIK3R1 expression in male patients. Journal of experimental & clinical cancer research : CR 47 29208003
2019 CircRNA AFF4 promotes osteoblast cells proliferation and inhibits apoptosis via the Mir-7223-5p/PIK3R1 axis. Aging 46 31848327
1999 Intermolecular interactions of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase. The Journal of biological chemistry 45 10212202
2021 Somatic PIK3R1 variation as a cause of vascular malformations and overgrowth. Genetics in medicine : official journal of the American College of Medical Genetics 43 34040190
2020 Antagonistic effect of selenium on lead-induced neutrophil apoptosis in chickens via miR-16-5p targeting of PiK3R1 and IGF1R. Chemosphere 42 31918102
2022 The Impact of PIK3R1 Mutations and Insulin-PI3K-Glycolytic Pathway Regulation in Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 41 35670774
2008 In brain, Axl recruits Grb2 and the p85 regulatory subunit of PI3 kinase; in vitro mutagenesis defines the requisite binding sites for downstream Akt activation. Journal of neurochemistry 41 18346204
2008 Association between phosphatidylinositol 3-kinase regulatory subunit p85alpha Met326Ile genetic polymorphism and colon cancer risk. Clinical cancer research : an official journal of the American Association for Cancer Research 40 18245521
2001 Direct interaction between the cytoplasmic tail of ADAM 12 and the Src homology 3 domain of p85alpha activates phosphatidylinositol 3-kinase in C2C12 cells. The Journal of biological chemistry 40 11313349
2001 Association of phosphatidylinositol 3-kinase composed of p110beta-catalytic and p85-regulatory subunits with the small GTPase Rab5. Journal of biochemistry 40 11432782
2019 Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer. Nature communications 39 30755611
2005 Specific role for p85/p110beta in GTP-binding-protein-mediated activation of Akt. The Biochemical journal 39 16091017
2017 PAK4 interacts with p85 alpha: implications for pancreatic cancer cell migration. Scientific reports 37 28205613
2015 Oncogenic mutations weaken the interactions that stabilize the p110α-p85α heterodimer in phosphatidylinositol 3-kinase α. The FEBS journal 37 26122737
2024 N6-methyladenosine-modified circPLPP4 sustains cisplatin resistance in ovarian cancer cells via PIK3R1 upregulation. Molecular cancer 36 38184597
2018 miR-486-5p regulates the migration and invasion of colorectal cancer cells through targeting PIK3R1. Oncology letters 36 29725442
2018 Overexpression of PIK3R1 promotes hepatocellular carcinoma progression. Biological research 35 30497511
2006 Galphaq binds to p110alpha/p85alpha phosphoinositide 3-kinase and displaces Ras. The Biochemical journal 34 16268778
2021 CBL mutations drive PI3K/AKT signaling via increased interaction with LYN and PIK3R1. Blood 32 33512474
2013 Cbl ubiquitination of p85 is essential for Epo-induced EpoR endocytosis. Blood 32 24113870
2011 Uncommon GNAQ, MMP8, AKT3, EGFR, and PIK3R1 mutations in thyroid cancers. Endocrine pathology 32 21487925
2001 Phosphatidylinositol 3-kinase p85 adaptor function in T-cells. Co-stimulation and regulation of cytokine transcription independent of associated p110. The Journal of biological chemistry 32 11679587
2008 Deletion of PI3K-p85alpha gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells. Genes and immunity 31 18548087
2001 Diversification of cardiac insulin signaling involves the p85 alpha/beta subunits of phosphatidylinositol 3-kinase. American journal of physiology. Endocrinology and metabolism 31 11120660
2015 p85α is a microRNA target and affects chemosensitivity in pancreatic cancer. The Journal of surgical research 30 25846727
2002 Characterization of the Met326Ile variant of phosphatidylinositol 3-kinase p85alpha. Proceedings of the National Academy of Sciences of the United States of America 30 11842213
1999 Ca(2+)/calmodulin and p85 cooperatively regulate an initiation of cytokinesis in Tetrahymena. Journal of cell science 29 10523498
2019 An oncogenic gene, SNRPA1, regulates PIK3R1, VEGFC, MKI67, CDK1 and other genes in colorectal cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 27 31203132
2019 Long noncoding RNA NEAT1 promotes the growth of gastric cancer cells by regulating miR-497-5p/PIK3R1 axis. European review for medical and pharmacological sciences 27 31486491
2018 MicroRNA-106a-5p Inhibited C2C12 Myogenesis via Targeting PIK3R1 and Modulating the PI3K/AKT Signaling. Genes 27 30004470
2020 A novel lncRNA LNC_000052 leads to the dysfunction of osteoporotic BMSCs via the miR-96-5p-PIK3R1 axis. Cell death & disease 26 32968049
2004 Altered splenic B cell subset development in mice lacking phosphoinositide 3-kinase p85alpha. International immunology 26 15520044
1995 Interaction of p85 subunit of PI 3-kinase with insulin and IGF-1 receptors analysed by using the two-hybrid system. FEBS letters 26 7589433
2019 Defining How Oncogenic and Developmental Mutations of PIK3R1 Alter the Regulation of Class IA Phosphoinositide 3-Kinases. Structure (London, England : 1993) 25 31831213
2017 Domain analysis reveals striking functional differences between the regulatory subunits of phosphatidylinositol 3-kinase (PI3K), p85α and p85β. Oncotarget 25 28915558
2015 Conjugation of SUMO to p85 leads to a novel mechanism of PI3K regulation. Oncogene 25 26411363
2008 Hyperactivity, memory deficit and anxiety-related behaviors in mice lacking the p85alpha subunit of phosphoinositide-3 kinase. Brain & development 25 18538520
2023 NLRP6 potentiates PI3K/AKT signalling by promoting autophagic degradation of p85α to drive tumorigenesis. Nature communications 24 37770465
2020 Truncation of Pik3r1 causes severe insulin resistance uncoupled from obesity and dyslipidaemia by increased energy expenditure. Molecular metabolism 24 32439336
2015 The PI3K regulatory subunit gene PIK3R1 is under direct control of androgens and repressed in prostate cancer cells. Oncoscience 24 26501081
2007 The p85alpha regulatory subunit of class IA phosphoinositide 3-kinase regulates beta-selection in thymocyte development. Journal of immunology (Baltimore, Md. : 1950) 23 17237381
2006 Nutritional upregulation of p85alpha expression is an early molecular manifestation of insulin resistance. Diabetologia 23 16491394
2022 MiR-486-5p Targets CD133+ Lung Cancer Stem Cells through the p85/AKT Pathway. Pharmaceuticals (Basel, Switzerland) 22 35337095
2020 Exogenous Therapeutics of Microrna-29a Attenuates Development of Hepatic Fibrosis in Cholestatic Animal Model through Regulation of Phosphoinositide 3-Kinase p85 Alpha. International journal of molecular sciences 22 32455716
2015 Assembly and Molecular Architecture of the Phosphoinositide 3-Kinase p85α Homodimer. The Journal of biological chemistry 22 26475863
2003 Src-dependent association of Cas and p85 phosphatidylinositol 3'-kinase in v-crk-transformed cells. Molecular cancer research : MCR 22 12692262
2024 Unveiling the role of PIK3R1 in cancer: A comprehensive review of regulatory signaling and therapeutic implications. Seminars in cancer biology 21 39197810
2019 Impact of p85α Alterations in Cancer. Biomolecules 21 30650664
2018 PIK3R1 gene polymorphisms are associated with type 2 diabetes and related features in the Turkish population. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 21 29893513
2016 p85α promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation. Oncotarget 21 26918608
2018 Interaction between CD133 and PI3K-p85 promotes chemoresistance in gastric cancer cells. American journal of translational research 20 29423015
2019 LSD1 Activates PI3K/AKT Signaling Through Regulating p85 Expression in Prostate Cancer Cells. Frontiers in oncology 19 31428587
2014 The double life of p85. Cancer cell 19 25314071
2012 IKK-β mediates hydrogen peroxide induced cell death through p85 S6K1. Cell death and differentiation 19 22955948
2011 p85alpha regulates osteoblast differentiation by cross-talking with the MAPK pathway. The Journal of biological chemistry 19 21324896