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)P3 to PI(4,5)P2 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)P3 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)P3 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 the PTEN:P-Rex2 interface that uncouple PTEN from the inhibition of Rac1 signaling.

Cardiomyocyte‐specific Peli1 contributes to the pressure overload‐induced cardiac fibrosis through miR ‐494‐3p‐dependent exosomal communication

“…Meanwhile, PTEN is a direct target of miR‐494 25,26 . As a tumor suppressor gene, PTEN regulates the proliferation, migration, and infiltration of tumor cells 27–30 . K. Miyoshi et al confirmed that PTEN in endothelial cells improved pulmonary fibrosis by regulating the AKT/ERK1/2 signaling pathway 31 .…”

A targetable PREX2/RAC1/PI3Kβ signalling axis confers resistance to clinically relevant therapeutic approaches in melanoma

“…1A). Given previous reports of the reciprocal inhibition between PREX2 and PTEN 24,25 , and the loss of PTEN expression frequently observed in human melanoma 29 , we investigated the impact of Prex2 deletion in models driven by loss of Pten , compared with loss of Trp53 (Fig. 1E; Supplementary Fig.…”

“…The corollary of these findings is that PTEN loss would upregulate the GEF activity of PREX2 and, consequently, stimulate RAC1 function, rendering targeting of PREX2 in the context of PTEN-deficient melanoma a rational approach. Intriguingly, the aforementioned melanoma-associated RAC1-activating mutations appear to be mutually exclusive with PTEN loss, suggesting a scenario whereby loss of PTEN relieves the inhibition of PREX2 24,25 . Conversely, PREX2 can inhibit PTEN, promoting cell proliferation and tumorigenesis by activating downstream PI3K/AKT signalling 23,25,26 (Fig.…”

“…Intriguingly, the aforementioned melanoma-associated RAC1-activating mutations appear to be mutually exclusive with PTEN loss, suggesting a scenario whereby loss of PTEN relieves the inhibition of PREX2 24,25 . Conversely, PREX2 can inhibit PTEN, promoting cell proliferation and tumorigenesis by activating downstream PI3K/AKT signalling 23,25,26 (Fig. 1A).…”

ARNO is recruited by the neuronal adaptor FE65 to potentiate ARF6-mediated neurite outgrowth

“…For instance, binding of Rabaptin-5 to Rabex-5 GEF leads to the exposure of the catalytic site for the activation of Rab5 GTPase [ 24 ]. Conversely, the autoinhibited conformation of P-Rex2 GEF for Rho GTPases is strengthened by an interaction with PTEN [ 33 ]. It has been proposed that the PH domain of cytohesin 1 plays a significant role in relieving the autoinhibited conformation [ 30 ].…”