Melanoma chondroitin sulphate proteoglycan regulates cell spreading through Cdc42, Ack-1 and p130cas.
Melanoma chondroitin sulphate proteoglycan (MCSP) is a cell-surface antigen that has been implicated in the growth and invasion of melanoma tumours. Although this antigen is expressed early in melanoma progression, its biological function is unknown. MCSP can stimulate the integrin-alpha4 beta1-mediated adhesion and spreading of melanoma cells. Here we show that stimulated MCSP recruits tyrosine-phosphorylated p130 cas, an adaptor protein important 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 p130cas. Furthermore, vectors inhibiting Ack-1 or Cdc42 expression and/or function abrogate MCSP-induced tyrosine phosphorylation and recruitment of p130cas. Our findings indicate that MCSP may modify tumour growth or invasion by a unique signal-transduction pathway that links Cdc42 activation to downstream tyrosine phosphorylation and subsequent cytoskeletal reorganization.
Eisenmann
K M
KM
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
McCarthy
J B
JB
Simpson
M A
MA
Keely
P J
PJ
Guan
J L
JL
Tachibana
K
K
Lim
L
L
Manser
E
E
Furcht
L T
LT
Iida
J
J
D002465:Cell Movement; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism*; D050719:Crk-Associated Substrate Protein; D004789:Enzyme Activation; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
C493841:BCAR1 protein, human; D011508:Chondroitin Sulfate Proteoglycans; D050719:Crk-Associated Substrate Protein; D039041:Integrin alpha4beta1; D016023:Integrins; D010750:Phosphoproteins; D011506:Proteins; D016201:Receptors, Lymphocyte Homing; D050717:Retinoblastoma-Like Protein p130; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human; D020764:cdc42 GTP-Binding Protein