Through the interaction with extracellular matrix proteins and proteases, TSP-1 and -2 have been shown to regulate matrix structure. At the cell surface, TSP-1 has been shown to regulate migration, proliferation and survival through the interaction with proteoglycans, integrins and CD36. The goal of our research is to obtain a detailed comprehension of the structure and function of the members of the TSP gene family. We are currently using X-ray crystallography to determine the structure of the various domains of these proteins. TSP-1 and -2 are potent endogenous inhibitors of angiogenesis and tumor progression. Ongoing experiments indicate that specific structures with in the type 1 repeats (TSRs) of TSP-1 and -2 mediate this activity. The effects of the TSRs on endothelial cell migration and apoptosis are mediated by the membrane protein CD36. We are currently working to identify signaling molecules and other membrane proteins that collaborate with CD36 to inhibit endothelial cell function. These studies may identify novel targets for the inhibition of angiogenesis and tumor growth. Tumor growth is also suppressed by the activation of transforming growth factor beta (TGF beta) by TSP-1 in the tumor microenvironment. The lab is currently working to determine the molecular basis for the activation of TGF beta by TSP-1. Using a genetic model of mammary adenocarcinoma, we have found that TSP-1 suppresses primary tumor growth, but promotes metastasis. Taken together, these data indicate that TSP-1 is a key regulator of the tissue remodeling that is associated with neoplasia. We are currently exploring the possibility that other members of the thrombospondin gene family have similar functions.
Cartilage oligomeric matrix protein (COMP) is the fifth member of the TSP gene family. COMP affects cellular attachment, proliferation, and influences chondrogenesis. It also affects extracellular matrix structure through interactions with collagens, matrilins, and proteoglycans. The importance of COMP to cartilage synthesis and function is underscored by findings that COMP mutations lead to pseudoachondroplasia and a subgroup of multiple epiphyseal dysplasia designated EDM1. The lab is using structural and biochemical approaches to identify functional sites within COMP for protein and proteoglycan binding. In addition, the effect of disease causing mutations on COMP structure and function are being explored.
Selected Recent Publications
Hamano Y, Sugimoto H, Soubasakos MA, Kieran M, Olsen BR, Lawler J, Sudhakar A, Kalluri R. Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression.
Cancer Research. 2004, 64:1570-1574.
Yee KO, Streit M, Hawighorst T, Detmar M, Lawler J
. Expression of the type-1 repeats of thrombospondin-1 inhibits tumor growth through activation of transforming growth factor-beta.
Am J Pathol. 2004; 165(2):541-552.
Zhang X, Galardi E, Duquette M, Delic M, Lawler J, Parangi S. Anti-angiogenic treatment with the three thrombospondin-1 type 1 repeats recombinant protein in an orthotopic human pancreatic cancer model.
Clin. Cancer Res. 2005. 11(6): 2337-2344.
Chen FH, Thomas AO, Hecht JT, Goldring MB, Lawler J. Cartilage oligomeric matrix protein/thrombospondin-5 supports chondrocyte attachment through interaction with integrins. J. Biol. Chem. 2005; 280(38): 32655-32661.
Tan K, Duquette M, Liu JH, Zhang R, Joachimiak A, Wang JH, Lawler J. The structures of the thrombospondin-1 N-terminal domain and its complex with a synthetic pentameric heparin. Structure. 2006; 14(1): 33-42.
Chen FH, Herndon ME, Patel N, Hecht JT, Lawler J. Interaction of cartilage oligomeric matrix protein/thrombospondin-5 with aggrecan. J. Biol. Chem. 2007; 282(34): 24591-24598.
Yee KO, Conolly CM, Duquette M, Kazerounian S, Washington R, Lawler J. The effect of thrombospondin-1 on breast cancer metastasis. Breast Cancer Res Treat 2008.
Lawler J. The functions of thrombospondin-1 and 2. undefinedCurrent Opinion in Cell Biology 2000, 12:634-640.
Adams J.C. and Lawler J, The Thrombospondins.
Inter. J. Biochem. Cell Biol. 2004: 36: 961-968.
Lawler J. and Detmar M. Tumor progression: The effects of thrombospondin-1 and -2.
Inter. J. Biochem. Cell Biol. 2004; 36; 1038-1045.
Zhang X, Lawler J. Thrombospondin-based anti-angiogenic therapy. Microvascular Research 2007: 74(2-3), 90-99.
Kazerounian S, Yee KO, Lawler J. Thrombospondins and cancer. Cell Mol. Life Sci. 2008: 65(5), 700-712.
Carlson CB, Lawler J, Mosher DF. Structures of thrombospondin. Cell Mol. Life Sci. 2008: 65(5), 672-686.
Schematic diagram of the thrombospondin gene family and the type 1 repeat superfamily: