CRKL Mediates p110?-Dependent PI3K Signaling in PTEN-Deficient Cancer Cells.

ABSTRACT: The p110? isoform of PI3K is preferentially activated in many tumors deficient in the phosphatase and tensin homolog (PTEN). However, the mechanism(s) linking PTEN loss to p110? activation remain(s) mysterious. Here, we identify CRKL as a member of the class of PI3K?-interacting proteins. Silencing CRKL expression in PTEN-null human cancer cells leads to a decrease in p110?-dependent PI3K signaling and cell proliferation. In contrast, CRKL depletion does not impair p110?-mediated signaling. Further study showed that CRKL binds to tyrosine-phosphorylated p130Cas in PTEN-null cancer cells. Since Src family kinases are known both to be regulated by PTEN and to phosphorylate and activate p130Cas, we tested and found that Src inhibition cooperated with p110? inhibition to suppress the growth of PTEN-null cells. These data suggest both a potential mechanism linking PTEN loss to p110? activation and the possible benefit of dual inhibition of Src and PI3K for PTEN-null tumors.

SUBMITTER: Zhang J 

PROVIDER: S-EPMC5704918 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature