MARCKS is an actin filament crosslinking protein regulated by protein kinase C and calcium–calmodulin

Abstract

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 identified³. 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^9,10and 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.