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Published 21 June 2004. doi:10.1083/jcb.200403174
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 6, 881-891
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Article

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

Jianbo Yang1, Matthew A. Price1, Cheryl L. Neudauer1, Christopher Wilson1, Soldano Ferrone4, Hong Xia2, Joji Iida1, Melanie A. Simpson1,3, and James B. McCarthy1

1 Department of Laboratory Medicine and Pathology and Comprehensive Cancer Center, University of Minnesota, Minneapolis, MN 55455
2 Department of Medicine, University of Minnesota, Minneapolis, MN 55455
3 Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588
4 Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263

Address correspondence to James B. McCarthy, University of Minnesota, Dept. of Laboratory Medicine and Pathology, 312 Church St. SE, Room 7-124 BSBE, Minneapolis, MN 55406. Tel.: (612) 625-7454. Fax: (612) 625-1121. email: mccar001{at}umn.edu

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 {alpha}4 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.

Key Words: melanoma chondroitin sulfate proteoglycan; FAK; integrin; ERK1/2; cell spreading

J. Yang and M.A. Price contributed equally to this paper.

Abbreviations used in this paper: cABC, chondroitinase ABC; ERK, extracellular signal–regulated kinase; FN, fibronectin; FRNK, focal adhesion–related nonkinase; MCSP, melanoma chondroitin sulfate proteoglycan; pERK, phosphorylated ERK; PG, proteoglycan; RGP, radial growth phase; SIFM, serum- and insulin-free medium; VGP, vertical growth phase.


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