Myristoylated alanine rich C kinase substrate (MARCKS) and its role in the pathogenesis of cancer.

Myristoylated alanine-rich C kinase substrate (MARCKS) is primarily phosphorylated by protein kinase C (PKC). Recently, we have shown that it is also phosphorylated upon stimulation of ErbB2 (also known as HER2). It is localized to the plasma membrane and is an actin filament cross-linking protein. Phosphorylation or binding to calcium-calmodulin disrupts its association with the plasma membrane, leading to its translocation to the cytoplasm. The protein is involved in structural modulation of the actin cytoskeleton, chemotaxis, motility, cell adhesion, phagocytosis, and exocytosis through lipid sequestering and/or protein docking to membranes. It exerts an influence on many physiological processes, for example, embryonic development, tissue regeneration, neuronal plasticity, and inflammation. Increasingly, the role of MARCKS in the pathogenesis of cancers is being appreciated. The increased expression of either MARCKS or its phosphorylated form is associated with many cancers and is correlated with an adverse outcome. However, in some, it functions as a tumor suppressor gene, and decreased expression correlates with a favorable outcome. Despite these associations from in vitro experiments and some xenograft studies, the role of MARCKS in malignant transformation is poorly understood. Interestingly, specific peptide inhibitors derived from MARCKS inhibit its function and are being evaluated in cancers. This review is a critical assessment of the role of MARCKS in the pathogenesis of cancers, clarifies unanswered questions and suggests the way forward for the future.