Recognition of CD146 as an ERM-binding protein offers novel mechanisms for melanoma cell migration

Abstract

Tumor cell migration is a well-orchestrated multistep process that drives cancer development and metastasis. 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. Here, we report 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. Thus, our results provide a mechanistic basis to understand the role of CD146 in regulating human melanoma cell motility.

Expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells regulates proliferation, differentiation, and maintenance of hematopoietic stem and progenitor cells

“…20,21,32 In agreement with these findings, we demonstrate that MCAM expression also affects the migration of hMSC ( Figure 1H). Luo et al suggested a possible molecular mechanism whereby MCAM may be involved in cytoskeleton remodeling and cell migration.…”

“…These authors demonstrated an association between MCAM and ERM proteins that further induced RhoA activation. 21 Other groups showed that inhibition of RhoA induces cell migration. 33 We found elevated RhoA activity in hMSC upon MCAM knockdown with induced stress fiber formation and reduced migration (Online Supplementary Figure S4).…”

Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension

“…2e). We have previously reported that CD146 promotes melanoma cell migration by activating small GTPase RhoA 18 . RhoA is an important component of the non-canonical Wnt pathway located downstream of Dvls.…”

“…Later on, CD146 was also identified as a factor in angiogenesis, and tumour cell invasion and migration [14][15][16][17] . We have previously reported that CD146 regulates cell migration through cytoskeleton proteins by activating the small GTPase RhoA 18 . However, the underlying mechanism of CD146 has remained elusive.…”

“…We previously reported that CD146 regulates melanoma cell migration by regulating the binding protein actin-linking ezrinradixin-moesin (ERM) 18 . Although ERM and Dvl both bind to CD146 at its cytoplasmic tail, their interaction with CD146 displays different properties: first, ERM binds to the positively charged region (KKGK) of CD146, whereas Dvl binds to a different region close to the KKGK motif; second, the binding of CD146 to ERM is constitutive.…”