The C-terminus of PRK2/PKNgamma is required for optimal activation by RhoA in a GTP-dependent manner |
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Authors: | Lim Wee Guan Chen Xiao Liu Jun-Ping Tan Bee Jen Zhou Shufeng Smith Adam Lees Nathaniel Hou Liansheng Gu Fukang Yu Xi Yong Du Yaomin Smith Derek Verma Chandra Liu Ke Duan Wei |
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Institution: | a Department of Biochemistry, Yong Loo Lin of Medicine, The National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore b Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China c Department of Immunology, Monash University Medical School, Prahran, Vic. 3181, Australia d Division of Chinese Medicine, School of Health Sciences, RMIT University, Bundoora, Vic. 3083, Australia e Department of Biology, East China Normal University, Shanghai 200062, PR China f Research Center of Medical Sciences, Guangdong Provincial People’s Hospital, Guangzhou 510080, PR China g Bioinformatics Institute, 30 Biopolis Street, Singapore 138671, Singapore h College of Life Sciences, Sichuan University, 24, South Section 1, Yihuan Road, Chengdu, Sichuan 610065, PR China i School of Medicine, Deakin University, Pigdons Road, Waurn Ponds, Vic. 3217, Australia |
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Abstract: | PRK2/PKNγ is a Rho effector and a member of the protein kinase C superfamily of serine/threonine kinases. Here, we explore the structure-function relationship between various motifs in the C-terminal half of PRK2 and its kinase activity and regulation. We report that two threonine residues at conserved phosphoacceptor position in the activation loop and the turn motif are essential for the catalytic activity of PRK2, but the phosphomimetic Asp-978 at hydrophobic motif is dispensable for kinase catalytic competence. Moreover, the PRK2-Δ958 mutant with the turn motif truncated still interacts with 3-phosphoinositide-dependent kinase-1 (PDK-1). Thus, both the intact hydrophobic motif and the turn motif in PRK2 are dispensable for the binding of PDK-1. We also found that while the last seven amino acid residues at the C-terminus of PRK2 are not required for the activation of the kinase by RhoA in vitro, however, the extreme C-terminal segment is critical for the full activation of PRK2 by RhoA in cells in a GTP-dependent manner. Our data suggest that the extreme C-terminus of PRK2 may represent a potential drug target for effector-specific pharmacological intervention of Rho-medicated biological processes. |
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Keywords: | PRK2 PKC Rho PDK-1 Signal transduction |
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