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

Jing Zhang1, Xueliang Gao1, Fabienne Schmit1

  • 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.

Cell Reports
|July 21, 2017
PubMed

Insights

Loss of PTEN tumor suppressor leads to activation of PI3K-p110β signaling via CRKL. Dual inhibition of Src and PI3K shows promise for treating PTEN-null cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Phosphatidylinositol 3-kinase (PI3K) pathway dysregulation is common in cancer.
  • The p110β isoform of PI3K is often activated in tumors lacking the phosphatase and tensin homolog (PTEN).
  • The precise mechanisms connecting PTEN loss to p110β activation are not well understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms linking PTEN loss to PI3K-p110β activation.
  • To identify novel proteins involved in this signaling axis.
  • To explore potential therapeutic strategies for PTEN-null tumors.

Main Methods:

  • CRKL protein interaction studies in PTEN-null human cancer cells.
  • CRKL gene silencing experiments to assess PI3K signaling and proliferation.
  • Analysis of CRKL binding to p130Cas in PTEN-null cells.
  • Investigating the role of Src family kinases in this pathway.
  • Evaluating the efficacy of combined Src and PI3K inhibition.

Main Results:

  • CRKL was identified as a PI3Kβ-interacting protein.
  • Silencing CRKL reduced p110β-dependent PI3K signaling and proliferation in PTEN-null cells.
  • CRKL binds to tyrosine-phosphorylated p130Cas in PTEN-null cancer cells.
  • Src inhibition combined with p110β inhibition suppressed tumor cell growth.
  • CRKL depletion did not affect p110α-mediated signaling.

Conclusions:

  • CRKL acts as a mediator linking PTEN loss to PI3K-p110β activation.
  • The Src-p130Cas-CRKL axis is implicated in PTEN-null cancer progression.
  • Combined inhibition of Src and PI3Kβ represents a potential therapeutic approach for PTEN-deficient tumors.
Keywords:
CRKLPI3KPTENSrccancerp110βp130Casproliferationprotein interactionsignaling

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