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J. Cell Sci. 117 (19): 4469-4479

Research Article

The bi-directional translocation of MARCKS between membrane and cytosol regulates integrin-mediated muscle cell spreading

Marie-Hélène Disatnik1,*, Stéphane C. Boutet1,*, Wilfred Pacio1, Annie Y. Chan1, Lindsey B. Ross1, Christine H. Lee1, and Thomas A. Rando1,2,{ddagger}

1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5235, USA
2 GRECC and Neurology Service, Veterans Affairs Palo Alto Heath Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA

{ddagger} Author for correspondence (e-mail: rando{at}stanford.edu)

Accepted for publication 11 May 2004.

Abstract: The regulation of the cytoskeleton is critical to normal cell function during tissue morphogenesis. Cell-matrix interactions mediated by integrins regulate cytoskeletal dynamics, but the signaling cascades that control these processes remain largely unknown. Here we show that myristoylated alanine-rich C-kinase substrate (MARCKS) a specific substrate of protein kinase C (PKC), is regulated by {alpha}5ß1 integrin-mediated activation of PKC and is critical to the regulation of actin stress fiber formation during muscle cell spreading. Using MARCKS mutants that are defective in membrane association or responsiveness to PKC-dependent phosphorylation, we demonstrate that the translocation of MARCKS from the membrane to the cytosol in a PKC-dependent manner permits the initial phases of cell adhesion. The dephosphorylation of MARCKS and its translocation back to the membrane permits the later stages of cell spreading during the polymerization and cross-linking of actin and the maturation of the cytoskeleton. All of these processes are directly dependent on the binding of {alpha}5ß1 integrin to its extracellular matrix receptor, fibronectin. These results demonstrate a direct biochemical pathway linking {alpha}5ß1 integrin signaling to cytoskeletal dynamics and involving bi-directional translocation of MARCKS during the dramatic changes in cellular morphology that occur during cell migration and tissue morphogenesis.

Key Words: Integrin • PKC • Muscle • MARCKS • Actin • Fibronectin

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