CRKL Mediates p110β-Dependent PI3K Signaling in PTEN-Deficient Cancer Cells

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Jing Zhang, Xueliang Gao, Fabienne Schmit, Guillaume Adelmant, Michael J. Eck, Jarrod A. Marto, Jean J. Zhao, Thomas M. Roberts
The p110β 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 p110β activation remain(s) mysterious. Here, we identify CRKL as a member of the class of PI3Kβ-interacting proteins. Silencing CRKL expression in PTEN-null human cancer cells leads to a decrease in p110β-dependent PI3K signaling and cell proliferation. In contrast, CRKL depletion does not impair p110α-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 p110β inhibition to suppress the growth of PTEN-null cells. These data suggest both a potential mechanism linking PTEN loss to p110β activation and the possible benefit of dual inhibition of Src and PI3K for PTEN-null tumors.

Graphical abstract

Teaser

Zhang et al. find a role for CRKL in regulating p110β-dependent PI3K activity in PTEN-null cancer cells through its association with p110β/p85. A PTEN/FAK/Src/p130Cas axis may activate CRKL/p110β in PTEN-null cancer cells. Src inhibition cooperates with PI3K or p110β inhibition to suppress the growth of PTEN-null tumor cells.


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