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Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
Published on: July 17, 2020
PHLPP is neither a Phosphatase nor a Tumor Suppressor
1Max Perutz Labs, Medical University of Vienna, Vienna, Austria.
Summary
PH domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1/PHLPP2), long considered Akt phosphatases and tumor suppressors, may be pseudophosphatases lacking catalytic activity. This challenges their established roles and necessitates re-evaluating their biological functions.
Area of Science:
- Cellular signaling
- Molecular biology
- Cancer research
Background:
- PH domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1/PHLPP2) have been extensively studied as Akt phosphatases.
- These proteins have been widely recognized for their tumor suppressor gene functions in numerous publications.
- Previous research focused on pharmacologically inhibiting PHLPP in various disease contexts.
Purpose of the Study:
- To critically examine the evidence supporting the phosphatase activity and tumor suppressor roles of PHLPP1 and PHLPP2.
- To address the implications of recent findings suggesting PHLPP1/PHLPP2 are pseudophosphatases.
- To propose new hypotheses and research directions for understanding the biological functions of these proteins.
Main Methods:
- Literature review and critical analysis of existing studies on PHLPP1 and PHLPP2.
- Examination of biochemical and genetic evidence regarding PHLPP catalytic activity.
- Synthesis of current understanding and proposal of future research avenues.
Main Results:
- Recent evidence suggests PHLPP1 and PHLPP2 may function as pseudophosphatases, lacking enzymatic activity.
- This challenges the long-standing paradigm of PHLPPs as direct Akt phosphatases.
- The reported tumor suppressor functions are now under scrutiny due to these findings.
Conclusions:
- The designation of PHLPP1 and PHLPP2 as pseudophosphatases requires a re-evaluation of their established roles in cancer.
- New hypotheses are needed to explain the biological functions of PHLPP1 and PHLPP2 beyond enzymatic activity.
- Further research is crucial to elucidate the true signaling roles of these ancient proteins.
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