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

• Published in: bioRxiv
• Main Authors: D'andrea, Laura, Lucato, Christina M, Marquez, Elsa A, Yong-Gang, Chang, Civciristov, Srgjan, Huang, Cheng, Elmlund, Hans, Schittenhelm, Ralf B, Mitchell, Christina A, Whisstock, James C, Halls, Michelle L, Ellisdon, Andrew M
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 13.04.2020
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Cancer; Cell proliferation; Conformation; G protein-coupled receptors; Mass spectroscopy; Metastases; Metastasis; Mutation; Phosphatidylinositol 3,4,5-triphosphate; PTEN protein; Rac1 protein
• DOI: 10.1101/2020.04.11.036434

The PTEN:P-Rex2 complex is one of the most commonly mutated signaling nodes 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 cell proliferation. Here, using extensive crosslinking mass spectrometry and functional studies, we provide crucial mechanistic insights into PTEN:P-Rex2 complex assembly and co-inhibition. PTEN is anchored to P-Rex2 by interactions between the PTEN PDZ-BM tail and the second PDZ domain of P-Rex2. This interaction bridges PTEN across the P-Rex2 surface, occluding PTEN membrane-binding and PI(3,4,5)P3 hydrolysis. Conversely, PTEN both allosterically promotes an autoinhibited P-Rex2 conformation and occludes Gβγ binding and GPCR activation. These insights allow us to define a new gain-of-function class of cancer mutations within the PTEN:P-Rex2 interface that uncouples PTEN inhibition of Rac1 signaling. These findings provide a mechanistic framework to understand the dysregulation of the PTEN:P-Rex2 signaling node in metastatic cancer. Competing Interest Statement The authors have declared no competing interest.