期刊
SCIENCE SIGNALING
卷 14, 期 681, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.abc4078
关键词
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资金
- Australian Postgraduate Award
- Monash Golden Jubilee Postgraduate Research Award
- NHMRC RD Wright Fellowship [1061687]
- Monash Fellowship
- NHMRC [APP1104614, APP1146578, APP1128120]
- office of the Vice-Provost for Research and Research Infrastructure (VPRRI) at Monash University
- Bioplatforms Australia (BPA) as part of the National Collaborative Research Infrastructure Strategy (NCRIS)
- National Health and Medical Research Council of Australia [1061687] Funding Source: NHMRC
The PTEN:P-Rex2 complex assembly inhibits the activity of both proteins and dysregulation can drive PI3K-AKT signaling and cellular proliferation. The study revealed the interactions between PTEN and P-Rex2, proposing a class of gain-of-function mutations within the PTEN:P-Rex2 interface that uncouple PTEN from the inhibition of Rac1 signaling.
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 G beta gamma 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 G beta gamma. 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.
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