Tumor cell migration is a well-orchestrated multistep process that drives cancer development and metastasis. CD146, also known as MCAM, MUC18, A32 antigen and S-Endo-1, is an integral membrane glycoprotein and belongs to the immunoglobulin superfamily. Although the extracellular ligand for CD146 is still unidentified, several studies have validated its functions in mediating the transduction of outside–in signals. Previous data indicated that CD146 expression correlates with malignant progression and metastatic potential of human melanoma cells. However, the exact molecular mechanism of how CD146 promotes melanoma cell migration still remains poorly understood.

Professor Xiyun Yan’s group at the Institute of Biophysics, Chinese Academy of Sciences has conducted in-depth study on CD146 for many years. Professor Yan and her colleagues found that CD146 mediates tumor secretion-induced p38/IκB kinase/nuclear factor-κB signaling cascade, which is pivotal in inducing endothelial cell activation, leading to tumor angiogenesis. Recently, they reported that CD146 physically interacts with actin-linking ezrin–radixin–moesin (ERM) proteins and recruits ERM proteins to cell protrusions, promoting the formation and elongation of microvilli. Moreover, CD146-promoted melanoma cell migration is linked to RhoA activation and ERM phosphorylation. CD146 recruits Rho guanine nucleotide dissociation inhibitory factors 1 (RhoGDI1) through ERM proteins and thus sequesters RhoGDI1 from RhoA, which leads to upregulated RhoA activity and increased melanoma cell motility. CD146-activated RhoA also promotes further ERM phosphorylation and activation through Rho-phosphatidylinositol-4-phosphate-5-kinase-phosphatidylinositol 4,5-biphosphate pathway, which reinforces CD146/ERM association. Their results provide a mechanistic basis to understand the role of CD146 in regulating human melanoma cell motility.

This work which recognizes CD146 as an ERM-binding protein and offers novel mechanisms for melanoma cell migration was published as an original article in the latest issue of Oncogene.