Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate |
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Authors: | Byung Hak Ha Matthew J. Davis Catherine Chen Hua Jane Lou Jia Gao Rong Zhang Michael Krauthammer Ruth Halaban Joseph Schlessinger Benjamin E. Turk Titus J. Boggon |
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Affiliation: | Departments of aPharmacology.;bGenetics.;dPathology, and;eDermatology, and;fYale Cancer Center, Yale University School of Medicine, New Haven, CT, 06520; and;cCollege of Life Science and Technology, Guangxi University, Nanning, Guangxi 530004, China |
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Abstract: | 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-XL 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 β-PIX SH3, can activate PAK4. We provide a unique understanding for type II PAK regulation. |
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Keywords: | autoregulation protein kinase RHO GTPase effector signaling |
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