Kaposi's sarcoma (KS) is the major neoplastic manifestation of AIDS. Prior data indicate that KS spindle cell growth and spread can be driven by cytokines like IL-6, oncostatin M, VEGF and bFGF as well as the HIV gene product TAT. HIV-1 TAT can bind to the FLK-1/KDR receptor for the vascular endothelial growth factor (VEGF), and contains a classical RGD sequence which may activate surface integrin receptors for fibronectin and vitronectin. Furthermore, the Kaposi's sarcoma herpes virus (KSHV)/human herpes virus type 8 (HHV-8) appears to be a """"""""molecular pirate"""""""" whose open reading frames encode homologs of IL-6, the chemokine MIP1 and an activated IL-8 chemokine receptor. Despite extensive studies on modulation of KS cell growth by these soluble mediators, relatively little is known about their signal transduction pathways. To that end, we have begun to characterize cytokine, chemokine and TAT signaling pathways in a permanent KS spindle cell line with authentic properties of primary cells. We observed that the related adhesion focal tyrosine kinase (RAFTK), a newly discovered signaling molecule, prominently participates in all three pathways, and transmits signals to the transcriptional apparatus and the cytoskeleton. Our overall aim is to characterize signal transduction pathways in KS spindle cells that mediate their growth and spread using RAFTK as a primary focus of study. We are assisted in these studies by having specific reagents against RAFTK as well as dominant-negative RAFTK mutants. We will seek first to identify the signaling molecules that associate with cytokine, chemokine and TAT surface receptors, then study how these molecules connect to RAFTK, and proceed to characterize mediators downstream of RAFTK which lead to cytoskeletal and transcriptional activation. This structured approach to characterize cytokine, chemokine and TAT signaling pathways and their functional roles in KS spindle cells should provide insight into the mechanisms of KS growth and spread.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA076950-02
Application #
2837801
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Freeman, Colette S
Project Start
1998-02-01
Project End
2002-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Wang, Jian-Feng; Liu, Zhong-Ying; Anand, Appakkudal R et al. (2004) Alpha-chemokine-mediated signal transduction in human Kaposi's sarcoma spindle cells. Biochim Biophys Acta 1691:129-39
Fernandis, Aaron Z; Cherla, Rama P; Ganju, Ramesh K (2003) Differential regulation of CXCR4-mediated T-cell chemotaxis and mitogen-activated protein kinase activation by the membrane tyrosine phosphatase, CD45. J Biol Chem 278:9536-43
Fernandis, Aaron Z; Cherla, Rama P; Chernock, Rebecca D et al. (2002) CXCR4/CCR5 down-modulation and chemotaxis are regulated by the proteasome pathway. J Biol Chem 277:18111-7
Cherla, R P; Ganju, R K (2001) Stromal cell-derived factor 1 alpha-induced chemotaxis in T cells is mediated by nitric oxide signaling pathways. J Immunol 166:3067-74
Chernock, R D; Cherla, R P; Ganju, R K (2001) SHP2 and cbl participate in alpha-chemokine receptor CXCR4-mediated signaling pathways. Blood 97:608-15
Munshi, N; Groopman, J E; Gill, P S et al. (2000) c-Src mediates mitogenic signals and associates with cytoskeletal proteins upon vascular endothelial growth factor stimulation in Kaposi's sarcoma cells. J Immunol 164:1169-74
Ganju, R K; Brubaker, S A; Chernock, R D et al. (2000) Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk. J Biol Chem 275:17263-8