PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE.
In three-dimensional matrices cancer cells move with a rounded, amoeboid morphology that is controlled by ROCK-dependent contraction of acto-myosin. In this study, we show that PDK1 is required for phosphorylation of myosin light chain and cell motility, both on deformable gels and in vivo. Depletion of PDK1 alters the localization of ROCK1 and reduces its ability to drive cortical acto-myosin contraction. This form of ROCK1 regulation does not require PDK1 kinase activity, but instead involves direct binding of PDK1 to ROCK1 at the plasma membrane; PDK1 competes directly with RhoE for binding to ROCK1. In the absence of PDK1, negative regulation by RhoE predominates, causing reduced acto-myosin contractility and motility. This work uncovers a novel non-catalytic role for PDK1 in regulating cortical acto-myosin and cell motility.
Pinner
Sophie
S
Tumour Cell Biology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK. Erik.Sahai@cancer.org.uk
Sahai
Erik
E
D000199:Actins / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D048430:Cell Shape / Q000502:physiology; D006801:Humans; D018994:Myosin Light Chains / Q000502:physiology; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011554:Pseudopodia / Q000502:physiology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D020741:rho GTP-Binding Proteins / Q000502:physiology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
D000199:Actins; D018994:Myosin Light Chains; C000631429:PDK1 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; C508705:RND3 protein, human; D020741:rho GTP-Binding Proteins