Metastasis is the multistep process by which cancer cells leave primary tumors and establish secondary sites. Cell migration is a key step in metastasis. Previous studies have shown that the serine/threonine kinase Protein Kinase C (PKC) is involved in the signaling pathways controlling migration. However the direct substrate of PKC is unknown. This study investigated the expression level of Myristoylated-Alanine Rich C Kinase Substrate (MARCKS) in murine melanoma cells. MARCKS, a substrate of PKC, has been shown to be regulator of the actin cytoskeleton. Since migration involves actin cytoskeletal arrangements, MARCKS could be the direct substrate of PKC. Confocal microscopy revealed that the actin cytoskeleton was disorganized in melanoma cells overexpressing a kinase-defective PKC alpha. Further, Western blot analysis showed reduced phosphorylation of MARCKS in melanoma cells displaying lower metastatic potential. These results suggest that both PKC alpha and MARCKS are key components in the signaling pathways governing migration.