Melanoma chondroitin sulfate proteoglycan (MCSP), also known as high molecular weight melanoma associated antigen (HMW-MAA) is large, highly antigenic cell surface proteoglycan that is dramatically upregulated in melanoma. MCSP is being actively pursued as a target for melanoma vaccine development due to its restricted expression and antigenic properties. Despite its potential clinical importance, relatively little is known about the role of MCSP in melanoma progression. Previous studies have implicated MCSP in adhesion, motility, or cellular growth control. He presents data to demonstrate that inhibition of MCSP expression by anti-sense oligonucleotides inhibits tumor invasion and growth in soft agar in vitro. He has demonstrated that MCSP functions as an adhesion molecule, in part by enhancing the activity of a4b1 integrin, a mediator of tumor invasion and arrest. In addition, he has identified a novel signaling pathway stimulated by MCSP. Activation of MCSP leads to the rapid association and tyrosine phosphorylation of p130cas, an adapter protein implicated in tumor motility and invasion. This signaling pathway also involves the association of MCSP with cdc42, a rho-family GTPase that mediates filopodial formation, cell motility and growth. Furthermore, Ack-1, a tyrosine kinase that associates with active (i.e., GTP bound) cdc42, is required for MCSP induced tyrosine phosphorylation of p130cas. Collectively the data are consistent with a model in which MCSP enhances tumor growth and invasion by sequestering intracellular components of a signaling complex in response to an external stimulus. In this application he will further define that signaling complex and study its importance for melanoma growth, invasion and metastasis. Additionally, although the MCSP sequence is published, it has not previously been cloned. He has recently amplified the full-length coding sequence for MCSP by RT-PCR of human melanoma mRNA and are in the process of expressing it in transfected melanoma cells which lack MCSP. This clone will enable them to examine the structural and functional relationships between MCSP, its extracellular stimuli, and its intracellular signal transduction. He proposes three specific aims: 1. To evaluate the importance of MCSP expression and function in the growth, invasion and metastasis of malignant melanoma cells. 2. To delineate the mechanism of Ack-1 in MCSP induced tyrosine phosphorylation of p130cas and to study this mechanism in the survival, growth and metastasis of malignant melanoma cells. 3. To define functional domains of the MCSP core protein required for signaling and melanoma growth, invasion and metastasis.
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