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bioRxiv · 10.1101/2020.04.11.036434

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

D'Andrea, L.·Lucato, C. M.·Marquez, E. A.·Chang, Y.-G.·Civciristov, S.·Huang, C.·Elmlund, H.·Schittenhelm, R. B.·Mitchell, C. A.·Whisstock, J. C.·Halls, M. L.·Ellisdon, A. M.
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Abstract

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 G{beta}{gamma} 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.

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D'Andrea, L., Lucato, C. M., Marquez, E. A., Chang, Y.-G., Civciristov, S., Huang, C., Elmlund, H., Schittenhelm, R. B., Mitchell, C. A., Whisstock, J. C., Halls, M. L., Ellisdon, A. M.. 2020-04-13. Structural analysis of the PTEN:P-Rex2 signalling node reveals how cancer-associated mutations coordinate to hyperactivate Rac1. https://doi.org/10.1101/2020.04.11.036434

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