IndraLab

Statements

IRS1 binds PIK3CA. 59 / 59
1 4 | 4 50
sparser
"As shown in xref , the 30-AA mutant peptide inhibited the interaction between p110α E545K and IRS1 when added into cell lysates, whereas the WT peptide failed to cause any inhibition."
23643389
sparser
"Our data demonstrate that the p110α helical domain mutant proteins gain interaction with IRS1 in the absence of growth factor stimulation and that this mutant-specific protein interaction is independent of binding of p85 to phospho-IRS1 (see xref for our proposed model)."
23643389
sparser
"IRS1-p110α E545K interaction brings the mutant p110α to cytoplasmic membrane."
23643389
biogrid
No evidence text available
23604317
sparser
"This IRS1-p110α E545K interaction was validated by immunoprecipitation under serum-starvation conditions in three different settings."
23643389
reach
"We found that, when FBXL2 expression was silenced in NHFs, endogenous IRS1 bound more endogenous p85beta, but less p110alpha and p110beta (XREF_FIG)."
23604317
sparser
"It appeared that the p110α E545K-IRS1 interaction also did not require p85, as a truncated p110α E545K lacking the ABD domain required for p85 binding ( xref ) still associated with IRS1 ( xref and xref )."
23643389
sparser
"This action involved a PR (proline rich) domain-dependent interaction of PRR11 with the p85 regulatory subunit of PI3K which reduces homodimerization of p85 and, in turn, is permissive of ligand-induced association of p110α with insulin receptor substrate 1 (IRS1) and activation of PI3K. Ectopic expression of PRR11 failed to promote estrogen-independent growth when p110α was knocked down, and PRR11 -overexpressing cells were highly sensitive to PI3K inhibitors, suggesting that PRR11 amplification generates dependence on PI3K signaling, particularly in the setting of estrogen deprivation."
33127913
sparser
"Interestingly, as shown in xref , the stapled mutant peptide also inhibited the interaction between IRS1 and ΔABD p110α E545K. Thus this result provided further evidence that the protein interaction between IRS1 and p110α E545K mutant is not mediated by p85."
23643389
biogrid
No evidence text available
12933652
sparser
"In contrast, the corresponding stapled WT p110α peptide did not inhibit IRS1-p110α E545K interactions ( xref )."
23643389
signor
"Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin."
20966354
sparser
"Further, given that the mutant p110α-IRS1 interaction only exists in tumors harboring these mutations, it is likely that drugs targeting this interaction should have no or minimal toxicity."
23643389
sparser
"Disruption of the IRS1-p110α E545K interaction destabilizes the p110α protein, reduces AKT phosphorylation, and slows xenograft tumor growth of a cancer cell line expressing p110α E545K. Moreover, a hydrocarbon-stapled peptide that disrupts this interaction inhibits the growth of tumors expressing p110α E545K."
23643389
sparser
"Strikingly, our stapled mutant peptide almost completely disrupted the IRS1-p110α E545K interaction in cell lysates, but had no effects on p110α-p85 interaction ( xref )."
23643389
reach
"The p110alpha E545K mutant, but not the WT p110alpha, associates with IRS1."
23643389
sparser
"As shown in xref and xref , p110α E545K, but not the WT p110α, robustly associated with IRS1 under serum-starvation conditions in which tyrosine phosphorylation of IRS1 was undetectable, suggesting that the p110α E545K-IRS1 interaction is independent of IRS1 tyrosine phosphorylation."
23643389
sparser
"Our recent discovery that the helical domain p110α mutants directly interact with IRS1 may provide a more accessible target for developing drugs to treat cancer patients harboring those p110α mutations ( xref )."
24178578
sparser
"To test if IRS1 directly binds to p110α E545K, we expressed recombinant IRS1, WT p110α and p110α E545K in Sf9 cell and purified these proteins to homogeneity ( xref )."
23643389
sparser
"This mutation enables the abnormal interaction between p110α and insulin receptor substrate 1 (IRS1), which also stabilises p110α, but in a manner independent of signals controlling p85, resulting in constitutive activation of the PI3K pathway and increased cell proliferation, survival, and motility xref ."
30293088
sparser
"The p110α E545K-IRS1 interaction is required for in vivo tumor growth."
23643389
sparser
"Helical domain mutations increased catalytic activity by reducing the repression of p110α by p85α [ xref ] or facilitating the interaction of p110α with IRS-1 [ xref ], whereas kinase domain mutations increase the retention of p110α at the plasma membrane [ xref ]."
26881050
sparser
"We provide several pieces of evidence that the p110α E545K-IRS1 interaction plays a critical role in tumorigenesis."
23643389
sparser
"Further, both tyrosine and S632/635 phosphorylation of IRS-1 in PDZ-RhoGEF KO EWAT were decreased in response to insulin ( xref ), as was the direct association of IRS-1 with the p85α and p110α subunits of PI3K ( xref ), indicative of impeded insulin signaling throughput via IRS-1 ( xref ; xref )."
26512886
sparser
"Consistent with the notions that disruption of IRS1-p110α helical domain mutant protein interaction does not perturb AKT activation induced by growth factors, the mutant stapled peptide had no effect on AKT phosphorylation when these cell lines were stimulated by insulin ( xref )."
23643389
sparser
"This leads to a decrease in IRS-1 binding to phosphoinositide 3'-kinase and to the down-regulation of the phosphoinositide 3'-kinase/Akt pathway that mediates cell proliferation and survival."
11694516
sparser
"Indeed, when we assessed the amount of endogenous p85 and p110 that is associated with IRS-1 at either 2 min (before foci formation) or 20 min (after foci formed) after IGF-1 stimulation, we found that the level of IRS-1–bound p110α at 20 min post–IGF-1 stimulation was only 33% of that at 2 min."
16043515
sparser
"Our recent finding that p110α helical domain mutants gain direct interaction with IRS1 raises new hope of targeting this mutant specific protein interaction for cancer therapy."
24178578
sparser
"The p110α E545K mutant, but not the WT p110α, associates with IRS1."
23643389
sparser
"Importantly, knockout of IRS1 in the p110α E545K mutant only DLD1 cells reduced the amount of membrane-bound p110α mutant proteins ( xref ), supporting the conclusion that interaction between IRS1 and p110α E545K enhances the association of p110α E545K with the cytoplasmic membrane."
23643389
sparser
"Furthermore, neither the linear mutant peptide nor the stapled WT peptide affected the interaction between p110α E545K and IRS1 when added to cultured DLD1 cells ( xref ), providing strong support of the specificity and efficacy of the stapled mutant peptide."
23643389
sparser
"These results suggest that IRS1-p110α E545K interaction is crucial for the mutant p110α to exert its oncogenic functions."
23643389
sparser
"In contrast, neither of the single region deletions could interrupt IRS1-mutant p110α interaction ( xref )."
23643389
reach
"As shown in XREF_FIG and XREF_SUPPLEMENTARY, p110alpha E545K, but not the WT p110alpha, robustly associated with IRS1 under serum starvation conditions in which tyrosine phosphorylation of IRS1 was undetectable, suggesting that the p110alpha E545K-IRS1 interaction is independent of IRS1 tyrosine phosphorylation."
23643389
sparser
"We recently discovered that p110α helical domain mutant proteins, but not the kinase domain mutant proteins, directly associate with insulin receptor substrate 1 (IRS1)."
24178578
sparser
"The direct protein interaction between IRS1 and p110α helical domain mutants may provide a more accessible target for developing novel precision cancer therapy."
24178578
sparser
"The mechanism that is currently thought to explain the oncogenic effect of the E545K mutation is that the helical domain mutation weakens p110α’s interactions with the p85 regulatory subunits, which attenuates the inhibitory effect of p85 and thus increases the enzymatic activity of p110α [ xref , xref ] Moreover, another study suggested that the weakened p110α-p85 interaction caused by the mutation is not sufficient for the p110α mutant proteins to exert their oncogenic functions and provided several pieces of evidence that the p110α E545K-IRS1 interaction plays a critical role in tumorigenesis [ xref ]."
27317099
sparser
"As shown in xref and xref , recombinant IRS1 bound directly in vitro with p110α E545K but not WT p110α, providing further evidence that the IRS1-p110α E545K interaction is not mediated by p85 proteins."
23643389
sparser
"As shown in xref and xref , ablation of p85α and p85β enhanced rather than inhibited the interaction between p110α E545K and IRS1, suggesting that not only p85 proteins were not required but may compete with IRS1 for binding to p110α E545K. However, ablation of both p85 proteins led to destabilization of p110α protein ( xref )."
23643389
biogrid
No evidence text available
14511371
sparser
"It appears that the interaction between IRS1 and p110α E545K is required to stabilize p110α E545K, co-expression of IRS1 with p110α in Sf9 insect cells stabilizes p110α E545K but not the WT p110α ( xref and xref )."
23643389
sparser
"Together, our data suggest that p85 proteins are not required for the interaction between p110α E545K and IRS1 but still play a role in the protein complex through stabilization of the mutant p110α."
23643389
sparser
"Importantly, however, IRS1Δ did not affect IRS1-p85 interaction ( xref and xref ), providing further supporting evidence that IRS1-mutant p110α interaction does not require p85."
23643389
sparser
"We recently discovered that p110α helical domain mutant proteins, but not the kinase domain mutant proteins, directly associate with IRS1."
24178578
sparser
"Interaction between the helical domain mutant p110α and IRS1 does not require p85 or IRS1 phosphorylation."
23643389
sparser
"Given that p110α is normally brought to the IRS1 complex through the interaction between the SH2 domain of p85 and phosphorylated tyrosine (pY) residues of IRS1, it was important to determine whether the p110α E545K-IRS1 interaction required p85 and tyrosine phosphorylation of IRS1."
23643389
sparser
"Because our results indicated that the p110α E545K-IRS1 interaction is required for in vivo tumor growth of the mutant CRC cells, we set out to test whether p110α-derived peptides encompassing the mutation site could be constructed to disrupt this interaction."
23643389
biogrid
No evidence text available
16354680
sparser
"Putting together these data leads to the hypothesis that a single molecular impairment in the pathway of insulin signaling, including an incomplete interaction between PIK3CA (OMIM association number, 171834) and IRS1 , may lead to insulin resistance, as well as insulin secretion defect."
30884193
sparser
"Conversely, PRR11 overexpression enhanced the p110α-IRS1 association and p-AKT in MDA-MB-175VII cells (Fig.  xref )."
33127913
sparser
"Consistently, the IRS1-p110α interaction was also impaired in the xenograft tumors formed by the IRS1Δ reconstituted cells ( xref ), which led to reduced phosphorylation of AKT and Foxo1 proteins ( xref )."
23643389
sparser
"In support of earlier results, it was also notable that the stapled mutant peptide did slightly reduce the protein levels of p110α, but did not affect levels of p85 and IRS1 ( xref and xref ), providing further evidence that the protein interaction between mutant p110α and IRS1 stabilizes p110α."
23643389
sparser
"Furthermore, IRS1 strongly associated with mutant p110α in the mutant only DLD1 cells but its interaction with the WT p110α was barely detectable in the WT only cells ( xref and xref )."
23643389
reach
"Moreover, a mutant PI3K (p110alpha) peptide capable of disrupting p110alpha and IRS1 complexes inhibits mutant p110alpha activity and suppresses tumorigenicity [XREF_BIBR]."
27221039
sparser
"Next, we set out to develop a system to test whether disruption of IRS1-mutant p110α interaction affects tumorigenicity."
23643389
sparser
"We then tested if peptides corresponding to only one of the two α-helical motifs could inhibit interactions between the mutant p110α and IRS1."
23643389
sparser
"As shown in xref and xref , this mutant fragment still bound to p110α E545K, providing further evidence that the protein interaction between IRS1 and p110α E545K mutant is independent of IRS1 phosphorylation."
23643389
sparser
"Moreover, when IRS1 was immunoprecipitated from various DLD1 derivatives, p110α E545K predominantly associated with IRS1 ( xref and xref )."
23643389
sparser
"IGF signaling activates the insulin receptor substrate 1 protein (IRS1), which then binds to the regulatory subunit of phosphoinositide 3 kinase (PIK3) ( xref )."
24970089