Melanoma chondroitin sulfate proteoglycan enhances FAK and ERK activation by distinct mechanisms

Abstract

Melanoma chondroitin sulfate proteoglycan (MCSP) is an early cell surface melanoma progression marker implicated in stimulating tumor cell proliferation, migration, and invasion. Focal adhesion kinase (FAK) plays a pivotal role in integrating growth factor and adhesion-related signaling pathways, facilitating cell spreading and migration. Extracellular signal–regulated kinase (ERK) 1 and 2, implicated in tumor growth and survival, has also been linked to clinical melanoma progression. We have cloned the MCSP core protein and expressed it in the MCSP-negative melanoma cell line WM1552C. Expression of MCSP enhances integrin-mediated cell spreading, FAK phosphorylation, and activation of ERK1/2. MCSP transfectants exhibit extensive MCSP-rich microspikes on adherent cells, where it also colocalizes with α4 integrin. Enhanced activation of FAK and ERK1/2 by MCSP appears to involve independent mechanisms because inhibition of FAK activation had no effect on ERK1/2 phosphorylation. These results indicate that MCSP may facilitate primary melanoma progression by enhancing the activation of key signaling pathways important for tumor invasion and growth.

Roles of NG2 glial cells in diseases of the central nervous system

“…In addition, NG2 and α3β1 integrin are co-expressed and form a physical complex on the cell surface. Upon stimulation by phorbol-12-myristate-13-acetate (PMA) or PDGF, the motility of NG2-positive cells increases significantly compared to that of NG2-null cells [67,68] . Further investigation has shown that both PMA and PDGF trigger protein kinase C α (PKCα)-dependent phosphorylation of NG2 proteoglycan at Thr2256, and that this phosphorylation event is required for the increase of motility.…”

Regulation of high molecular weight-melanoma associated antigen (HMW-MAA) gene expression by promoter DNA methylation in human melanoma cells

“…These include the activation of small Rho family GTPase Cdc42 and of the adaptor protein p130cas (Eisenmann et al, 1999), as well as the association of HMW-MAA with membrane-type 3 matrix metalloproteinase on melanoma cells (Iida et al, 2001). Furthermore, elevated HMW-MAA expression in early tumors has been proposed to facilitate tumor progression by enhancing the activation of focal adhesion kinase (FAK) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) (Yang et al, 2004). The clinical relevance of these findings is indicated by the higher frequency of HMW-MAA expression in metastatic than in primary lesions in acral lentiginous melanoma (ALM), and by the association of HMW-MAA expression in primary ALM lesions with poor prognosis (Kageshita et al, 1991(Kageshita et al, , 1993.…”

NG2, a novel proapoptotic receptor, opposes integrin α4 to mediate anoikis through PKCα-dependent suppression of FAK phosphorylation

“…17 NG2 also regulates FAK and ERK activation by distinct mechanisms in human melanoma cells. 13 However, regulation of FAK phosphorylation through proteoglycans in apoptosis has not been studied, and the role of NG2 in regulating apoptosis by the ECM is unknown.…”

“…The chondroitin sulfate proteoglycan (CSPG) nerve/glial antigen 2 (NG2) and the a4b1 integrin have been proposed as coreceptors with distinct signaling roles in mediating the spread of melanoma cells on FN-coated surfaces. 12,13 Thus, NG2 might work in concert with a4b1 to regulate anoikis induced by an altered FN matrix.…”