Figure 2.

Chondroitin sulfate proteoglycan 4 (CSPG4) Signaling Pathways. CSPG4 functions to activate two major overlapping but distinct signaling cascades: integrin/focal adhesion kinase (FAK) signaling (A) and MAPK pathway signaling (B). Through these two branches, CSPG4 ultimately promotes tumor progression through a variety of cellular functions. (A) CSPG4 influences integrin function and signaling pathways. CSPG4 promotes Src-FAK complexing through its interaction with the scaffold protein Syntenin. This leads to FAK activation by Src, prompting a number of signaling cascades including FAK–integrin–extracellular matrix (ECM) complex assembly, activation of Rac through p130cas, and activation of the PI3K/AKT/NFκB signaling cascade; activation of these pathways mediate the effects of CSPG4 on cytoskeletal reorganization, survival, chemoresistance, and migration. Activation of MMPs by CSPG4 via direct binding to the CS chain leads to local invasion of cancer cells. CSPG4/NG2 can also enhance survival as a result of its constitutive activation of integrin-related signals. (B) CSPG4 promotes MAPK signaling through receptor tyrosine (RTK)-dependent and independent mechanisms. In human melanomas, CSPG4 impacts activation of the ERK 1,2 pathway, likely by impacting on the growth factor-induced activation of RTKs. Note the expression of BRAF^V600E in this pathway, which results in the constitutive activation of this kinase (see text). In human melanoma cells expressing this BRAF-activating mutation, constitutive activation of the ERK 1,2 pathway requires the presence of CSPG4. There are several possible downstream oncogenic targets of the ERK 1,2 pathway, including MITF and activated c-Met, which are implicated in epithelial to mesenchymal transition. Inhibition of IKK by ERK 1,2 downstream of CSPG4 could also lead to cell survival and chemoresistance.