Research ArticleBiochemistry

Structural analysis of the PTEN:P-Rex2 signaling complex reveals how cancer-associated mutations coordinate to hyperactivate Rac1

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Science Signaling  04 May 2021:
Vol. 14, Issue 681, eabc4078
DOI: 10.1126/scisignal.abc4078

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Ramping up Rac1 for metastasis

The phosphatase and tumor suppressor PTEN hydrolyzes the lipid second messenger PI(3,4,5)P3, thereby suppressing cellular proliferation mediated by the PI3K-Akt pathway. The protein P-Rex2 activates Rac members of the Rho GTPase family to promote cell migration, invasion, and metastasis. Because PTEN and P-Rex2 bind to each other to form a coinhibitory complex, D’Andrea et al. used cross-linking mass spectrometry and functional studies to characterize the regions within each protein that were necessary for complex formation. The authors found that cancer-associated mutations in both proteins combined to enhance the activation of Rac1. Together, these findings enhance our understanding of the dysregulation of the PTEN:P-Rex2 complex that occurs in metastasis.

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