IndraLab
Statements
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 )."
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."
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."
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."
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."
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."
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 ."
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."
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 )."
sparser
"Phosphatidylinositol 3-kinase α (PI3Kα) is involved in cell proliferation forming interactions with adapter proteins such as insulin receptor substrate 1 (IRS1) in the presence of growth factor stimulation, stimulating the catalytic activity of PI3Kα. xref The two most common mutations found in cancer (E545K and H1047R) were explored experimentally identifying IRS1 as a binder of E545K mutant protein but not of H1074R mutant protein in pull-down experiments. xref It was also shown that the interaction of E545K mutant PI3Kα with IRS1 is required for the growth of colon cancer cells in vivo ."
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 ]."
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."
sparser
"Our analysis revealed that mRNA expression of the insulin signalling pathway Insr , Ins1 ; and Pik3ip1 (encoding the insulin receptor (IR), insulin receptor substrate-1 (INS1) and phospho-inositide-3-kinase interacting protein 1 (PIK3IP1), respectively), glucose uptake Slc2a4 (encoding for glucose transporter type 4 (GLUT4)), calcium cycle Cacna1s and Gjc2 (encoding for calcium voltage-gated channel subunit alpha1 S (CACNA1S) and connexin-47, respectively), calcium-dependent cardiac con-tractility Myh3 (encoding miosina-3), as well as cholesterol efflux Abca1 (encoding the ABCA1 transporter) showed a differential expression with a significant reduction by aggLDL and increased expression induced by insulin (Fig. xref )."
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."
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 )."
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."