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Chondroitin sulfate proteoglycan 4 enhanced melanoma motility and growth requires a cysteine in the core protein transmembrane domain

Yang, Jianboa; Price, Matthew A.a; Wanshura, Leah E.C.e; He, Jinsongf; Yi, Meig; Welch, Danny R.d; Li, Guiyuang; Conner, Seanb; Sachs, Jonathanc; Turley, Eva A.h; McCarthy, James B.a

doi: 10.1097/CMR.0000000000000574
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Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface proteoglycan that enhances malignant potential in melanoma and several other tumor types. CSPG4 functions as a transmembrane scaffold in melanoma cells to activate oncogenic signaling pathways such as focal adhesion kinase (FAK) and extracellular signal regulated kinases 1,2, that control motility, invasion and anchorage independent growth. Here, we demonstrate that CSPG4 promotes directional motility and anchorage independent growth of melanoma cells by organizing and positioning a signaling complex containing activated FAK to lipid rafts within the plasma membrane of migrating cells. This FAK-containing signal transduction platform, which consists of syntenin-1, active Src and caveolin-1 requires the cytoplasmic domain of CSPG4 for assembly. Enhanced directional motility promoted by this complex also requires a CSPG4 transmembrane cysteine residue C2230. Substituting C2230 with alanine (CSPG4C2230A) still permits assembly of the signaling complex, however Src remains in an inactive state. CSPG4C2230A also fails to promote anchorage independent growth and activation of extracellular signal regulated kinases 1,2. Therapies that target the transmembrane domain of CSPG4 could be a novel strategy for limiting progression by disrupting its function as a compartmentalized motogenic and growth-promoting oncogenic signaling node.

aDepartment of Laboratory Medicine and Pathology, University of Minnesota Masonic Cancer Center

bDepartment of Genetics, Cell Biology and Development

cDepartment of Biomedical Engineering, Center for Engineering in Medicine, University of Minnesota, Minneapolis, Minnesota

dDepartment of Cancer Biology, University of Kansas, Lawrence, Kansas

eResearch and Innovation Office, University of Colorado Boulder, Boulder, Colorado, USA

fDepartment of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen

gCancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China

hDepartment of Oncology/Biochemistry and London Regional Cancer Program, London Health Sciences Center, University of Western Ontario, Ontario, Canada

Received 17 July 2018 Accepted 17 December 2018

Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website, www.melanomaresearch.com.

Correspondence to James B. McCarthy, PhD, Department of Laboratory Medicine and Pathology, University of Minnesota Masonic Cancer Center, Minneapolis, MN 55455, USATel: +1 612 625 7454; fax: + 1 612 626 2696; e-mail: mccar001@umn.edu

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