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

Abstract

The dual-specificity phosphatase PTEN functions as a tumor suppressor by hydrolyzing PI(3,4,5)P ₃ to PI(4,5)P ₂ to inhibit PI3K-AKT signaling and cellular proliferation. P-Rex2 is a guanine nucleotide exchange factor for Rho GTPases and can be activated by Gβγ subunits downstream of G protein–coupled receptor signaling and by PI(3,4,5)P ₃ downstream of receptor tyrosine kinases. The PTEN:P-Rex2 complex is a commonly mutated signaling node in metastatic cancer. Assembly of the PTEN:P-Rex2 complex inhibits the activity of both proteins, and its dysregulation can drive PI3K-AKT signaling and cellular proliferation. Here, using cross-linking mass spectrometry and functional studies, we gained mechanistic insights into PTEN:P-Rex2 complex assembly and coinhibition. We found that PTEN was anchored to P-Rex2 by interactions between the PDZ-interacting motif in the PTEN C-terminal tail and the second PDZ domain of P-Rex2. This interaction bridged PTEN across the P-Rex2 surface, preventing PI(3,4,5)P ₃ hydrolysis. Conversely, PTEN both allosterically promoted an autoinhibited conformation of P-Rex2 and blocked its binding to Gβγ. In addition, we observed that the PTEN-deactivating mutations and P-Rex2 truncations combined to drive Rac1 activation to a greater extent than did either single variant alone. These insights enabled us to propose a class of gain-of-function, cancer-associated mutations within themore » PTEN:P-Rex2 interface that uncouple PTEN from the inhibition of Rac1 signaling.« less

Authors:

D’Andrea, Laura ^[1]; Lucato, Christina M. ^[1]; Marquez, Elsa A. ^[1]; Chang, Yong-Gang ^[1]; Civciristov, Srgjan ^[2]; Mastos, Chantel ^[2]; Lupton, Christopher J. ^[1]; Huang, Cheng ^[3]; Elmlund, Hans ^[1]; Schittenhelm, Ralf B. ^[3]; Mitchell, Christina A. ^[1]; Whisstock, James C. ^[4]; Halls, Michelle L. ^[2]; Ellisdon, Andrew M. ^[1]

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+ Show Author Affiliations

1. Biomedicine Discovery Institute, Monash University, Clayton, 3800 Victoria, Australia.
2. Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052 Victoria, Australia.
3. Biomedicine Discovery Institute, Monash University, Clayton, 3800 Victoria, Australia., Monash Proteomics & Metabolomics Facility, Monash University, Clayton, 3800 Victoria, Australia.
4. Biomedicine Discovery Institute, Monash University, Clayton, 3800 Victoria, Australia., ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, 3800 Victoria, Australia.

Publication Date:

Tue May 04 00:00:00 EDT 2021

Sponsoring Org.:

USDOE

OSTI Identifier:

1781847

Resource Type:

Published Article

Journal Name:

Science Signaling

Additional Journal Information:

Journal Name: Science Signaling Journal Volume: 14 Journal Issue: 681; Journal ID: ISSN 1945-0877

Publisher:

American Association for the Advancement of Science (AAAS)

Country of Publication:

United States

Language:

English