Melanoma chondroitin sulphate proteoglycan regulates cell spreading through Cdc42, Ack-1 and p130(cas)

Melanoma chondroitin sulphate proteoglycan (MCSP) is a cell-surface antigen that has been implicated in the growth and invasion of melanoma tumours, A lthough this antigen is expressed early in melanoma progression, its biolog ical function is unknown. MCSP can stimulate the integrin-alpha(4)beta(1)-m ediated adhesion and spreading of melanoma cells. Here we show that stimula ted MCSP recruits tyrosine-phosphorylated p130(cas), an adaptor protein imp ortant in tumour cell motility and invasion. MCSP stimulation also results in a pronounced activation and recruitment of the Rho-family GTPase Cdc42. MCSP-induced spreading of melanoma cells is dependent upon active Cdc42, a Cdc42-associated tyrosine kinase (Ack-1) and tyrosine phosphorylation of p1 30(cas). Furthermore, vectors inhibiting Ack-1 or Cdc42 expression and/or f unction abrogate MCSP-induced tyrosine phosphorylation and recruitment of p 130(cas). Our findings indicate that MCSP may modify tumour growth or invas ion by a unique signal-transduction pathway that links Cdc42 activation to downstream tyrosine phosphorylation and subsequent cytoskeletal reorganizat ion.