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Updated: Nov 6, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

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

Laura D'Andrea1, Christina M Lucato1, Elsa A Marquez1

  • 1Biomedicine Discovery Institute, Monash University, Clayton, 3800 Victoria, Australia.

Science Signaling
|May 5, 2021
PubMed

Insights

The PTEN:P-Rex2 complex, a cancer-associated signaling node, inhibits both proteins. Mutations in this complex can drive cancer by disrupting PTEN

Area of Science:

  • Molecular Biology
  • Cancer Signaling
  • Enzymology

Background:

  • PTEN (Phosphatase and tensin homolog) is a tumor suppressor that inhibits PI3K-AKT signaling by hydrolyzing phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3).
  • P-Rex2 is a guanine nucleotide exchange factor activated by Gβγ subunits and PI(3,4,5)P3.
  • The PTEN:P-Rex2 complex is frequently mutated in metastatic cancers, and its dysregulation promotes PI3K-AKT signaling and cellular proliferation.

Purpose of the Study:

  • To elucidate the mechanistic insights into the assembly and coinhibition of the PTEN:P-Rex2 complex.
  • To identify the structural basis for PTEN:P-Rex2 complex formation and its functional consequences.
  • To understand how mutations within the PTEN:P-Rex2 interface contribute to cancer progression.

Main Methods:

  • Cross-linking mass spectrometry to identify interaction sites within the PTEN:P-Rex2 complex.
  • Functional biochemical assays to assess the enzymatic activities of PTEN and P-Rex2.
  • Analysis of cancer-associated mutations in PTEN and P-Rex2.

Main Results:

  • PTEN binds to P-Rex2 via its C-terminal PDZ-interacting motif and P-Rex2's second PDZ domain, inhibiting PI(3,4,5)P3 hydrolysis.
  • PTEN allosterically promotes an autoinhibited conformation of P-Rex2 and blocks its Gβγ binding.
  • Combined PTEN-deactivating mutations and P-Rex2 truncations synergistically enhance Rac1 activation, suggesting gain-of-function mutations at the interface.

Conclusions:

  • The PTEN:P-Rex2 complex assembly is mediated by specific protein-protein interactions that lead to mutual inhibition.
  • Dysregulation of this complex through mutations can promote oncogenic signaling pathways, particularly Rac1 activation.
  • Understanding these interactions provides a basis for targeting the PTEN:P-Rex2 interface in cancer therapy.

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