Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 40, Pages 16107-16112Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1214447109
Keywords
autoregulation; protein kinase; RHO GTPase effector; signaling
Categories
Funding
- National Institutes of Health [GM102262, GM079498]
- China Scholarship Council [2011666003]
- Guangxi University
- Yale SPORE in Skin Cancer Grant [CA121974]
- Gilead Sciences Grant [YG-001-11]
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The type II p21-activated kinases (PAKs) are key effectors of RHO-family GTPases involved in cell motility, survival, and proliferation. Using a structure-guided approach, we discovered that type II PAKs are regulated by an N-terminal autoinhibitory pseudosubstrate motif centered on a critical proline residue, and that this regulation occurs independently of activation loop phosphorylation. We determined six X-ray crystal structures of either full-length PAK4 or its catalytic domain, that demonstrate the molecular basis for pseudosubstrate binding to the active state with phosphorylated activation loop. We show that full-length PAK4 is constitutively autoinhibited, but mutation of the pseudosubstrate releases this inhibition and causes increased phosphorylation of the apoptotic regulation protein Bcl-2/Bcl-X-L antagonist causing cell death and cellular morphological changes. We also find that PAK6 is regulated by the pseudosubstrate region, indicating a common type II PAK autoregulatory mechanism. Finally, we find Src SH3, but not beta-PIX SH3, can activate PAK4. We provide a unique understanding for type II PAK regulation.
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