MARCKS IS AN ACTIN FILAMENT CROSS-LINKING PROTEIN REGULATED BY PROTEIN-KINASE-C AND CALCIUM CALMODULIN

AGONISTS that stimulate protein kinase C (PKC) induce profound changes in cell morphology correlating with the reorganization of submembranous actin 1,2, but no direct connection between PKC and actin assembly has been identified 3. The myristoylated, alanine-rich C kinase substrate (MARCKS) binds calmodulin 4,5 and is a predominant, specific substrate of PKC which is phosphorylated during macrophage and neutrophil activation 6-8, growth factor-dependent mitogenesis 9,10 and neurosecretion 11,12; it is redistributed from plasma membrane to cytoplasm when phosphorylated 13-15 and is involved in leukocyte motility 14,15. Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin. MARCKS may be a regulated crossbridge between actin and the plasma membrane, and modulation of the actin crosslinking activity of the MARCKS protein by calmodulin and phosphorylation represents a potential convergence of the calcium-calmodulin and PKC signal transduction pathways in the regulation of the actin cytoskeleton.