Jack Lawler, PhD
Professor of Pathology
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN 270K
Boston, MA 02215
Lawler Lab >>
Jack Lawler received his PhD in Physics from Boston College in 1976, and performed postdoctoral training at the Dana Farber Cancer Center. Over the past 30 years, Dr. Lawler's laboratory has utilized a wide range of technologies to elucidate the structure and function of the thrombospondins. He has authored over 170 publications and has co-authored the book "The Thrombospondin Gene Family". In 1996, Dr. Lawler joined the Department of Pathology at the Beth Israel Deaconess Medical Center where he is currently the Director of the Division of Cancer Biology and Angiogenesis and Professor of Pathology at Harvard Medical School.
The Regulation of Tissue Remodeling and Angiogenesis by Thrombospondins (Tissue Remodeling and Angiogenesis by Thrombospondins)
The thrombospondins (TSPs) are a family of five extracellular, calcium-binding proteins that are important for the tissue remodeling that occurs during development, synaptogenesis, wound healing, angiogenesis and neoplasia. In addition, cartilage oligomeric matrix protein (COMP), also known as TSP-5, is a key regulator of the structure and function of cartilage. TSPs regulate extracellular matrix structure through interactions with matrix proteins and proteases. At the cell surface, TSP-1 affects migration, proliferation and survival through interactions 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, either alone or as complexes, with their ligands. TSP-1 and -2 are potent endogenous inhibitors of angiogenesis and tumor progression. Ongoing experiments indicate that specific structures within the type 1 repeats (TSRs) of TSP-1 and -2 mediate these effects. 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 ? (TGF-?) by TSP-1 in the tumor micro-environment. The lab is currently working to determine the molecular basis for the activation of TGF-? by TSP-1. Using a genetic model of mammary adenocarcinoma, we have found that TSP-1 suppresses primary tumor growth but promotes metastasis.
We have developed recombinant versions of the TSRs and shown that they are potent inhibitors of various types of cancer growth in model systems. The TSRs can be delivered by systemic injection of recombinant protein or by adeno-associated virus gene therapy approaches. The efficacy of combinations of the TSR recombinant proteins with other cancer therapeutics is currently under investigation.
New and Noteworthy Publications
View all publications via PubMed >>
Zhang X, Xu J,
Lawler J, Terwilliger E, Parangi S. Adeno-associated virus-mediated antiangiogenic gene therapy with thrombospondin-1 type 1 repeats and endostatin. Clin. Cancer Res. 2007; 13(13): 3968-3976.
This is the first study to use a TSR-based gene therapy approach for the inhibition of tumor growth.
Tan K, Duquette M, Liu J-h, Dong Y, Zhang R, Joachimiak A,
Lawler J, Wang J-h. Crystal structure of the TSP-1 type 1 repeats: a novel layered fold and its biological implications. J. Cell Biol. 2002. 159: 373-382. Drs. Wang and Lawler are corresponding authors.
To better understand the molecular basis for the inhibition of angiogenesis by TSP-1, we determined the structure of the TSRs by X-ray crystallography. The TSRs represent a novel ?-strand fold that is stabilized by cation- interactions between arginine and tryptophan residues.
Miao W-M, Seng WL, Duquette M, Lawler P, Laus C,
Lawler J. Thrombospondin-1 type 1 repeat recombinant proteins inhibit tumor growth through transforming growth factor-?-dependent and -independent mechanisms. Cancer Res. 2001. 61:7830-7839.
In this study, we established that the TSRs of TSP-1 inhibit tumor growth through the inhibition of angiogenesis and the activation of TGF-?.
Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SMF,
Lawler J, Hynes RO, Boivin GP, Bouck N. Thrombospondin-1 is a major activator of TGF-?1 in vivo. Cell, 1998; 93:1159-1170.
This study uses the TSP-1 deficient mice that were produced in the lab to show that TSP-1 is an endogenous activator of TGF-?.
Lawler J, Hynes RO. The structure of human thrombospondin, an adhesive glycoprotein with multiple calcium-binding sites and homologies with several different proteins. J Cell Biol. 1986; 103:1635-1648.
This is the first report of the cloning and sequencing of a member of the thrombospondin gene family. A novel amino acid sequence repeat that is present in many genes (the TSR) and the structural basis for high capacity calcium binding were identified in this study.