Suneel S. Apte, M.B.B.S., D.Phil. Profile Slides Publications Program

Research Program

The Apte laboratory has a broad interest in extracellular matrix and its regulation by metalloproteases and their inhibitors. The current focus is the ADAMTS superfamily, which includes ADAMTS proteases as well as non-proteolytic ADAMTS-like molecules. Of the 19 ADAMTS proteases, and 7 ADAMTS-like proteins, several were discovered or first characterized by this laboratory. We and others have identified significant functions for some of the molecules discovered in our lab.

ADAMTS proteases are charged with critical functions in organogenesis, angiogenesis, and maturation of molecules such as procollagen and pro-vWF. Dysregulation of ADAMTS proteases, (particularly ADAMTS5 and ADAMTS4) is a key pathological mechanism in arthritis.

Our ongoing work is of a fundamental nature, utilizing developmental biology, genetics and protein chemistry to obtain new insights on the role of ADAMTS proteases in mammalian development and human disease. This work is translatable to several human disorders such as arthritis, cancer, cardiovascular disorders and inherited connective tissue disorders, and uses relevant models of these disorders.

The current areas of emphasis are:

1. Functions of ADAMTS proteases in cardiovascular, musculoskeletal and craniofacial development, through analysis of knockouts with definitive roles in these processes.
ADAMTS proteases in human disorders: We study the role of ADAMTS10 in Weill- Marchesani syndrome and Marfan syndrome, and of ADAMTS3 in the Ehlers- Danlos syndrome type VIIC. Among acquired conditions, we have a strong interest in mechanisms of cartilage destruction in arthritis.
2. Biochemistry of ADAMTS proteases: We analyze post-translational regulatory mechanisms, undertake structure-function analysis, and seek new substrates and interactions of these proteases.
3. Biochemistry of ADAMTS-like proteins or punctins. We are using recombinant proteins and gene knockouts to investigate potential functions, post-translational modification and intermolecular interactions of this new family of secreted/ECM proteins.
4. Biological roles of MT1-MMP. We generated a MT1-MMP knockout many years ago in collaboration with Zhongjun Zhou, Karl Tryggvason and Raija Soininen. We continue to work on the developmental roles of MT1-MMP.

The Apte laboratory has benefited from collaborations with several other groups and with former post-doctoral fellows (see publications below). The laboratory has been the training ground for several young scientists from the US and abroad and welcomes inquiries from MDs or PhDs interested in post-doctoral training in any of its many areas of interest.

Publications

2007

Koo, B-H., Longpre, J-M., Alexander, J.P., Leduc, R., and Apte S.S. Regulation of ADAMTS9 secretion and its enzymatic activity by its propeptide. J Biol Chem , 2007, 282:16146-54

Wang, L.W., Dlugosz, M., Somerville, RPT., Raed, M., Haltiwanger, R.S., Apte, S.S. O- Fucosylation of thrombospondin type-1 repeats in ADAMTS-lik-1/punctin-1 regulates secretion: Implications for the ADAMTS superfamily. J Biol Chem , 2007;282:17024-31 (selected as paper of the week)

Mosig RA, Dowling O, Difeo A, Ramirez MC, Parker IC, Abe E, Diouri J, Aqeel AA, Wylie JD, Oblander SA, Madri J, Bianco P, Apte SS , Zaidi M, Doty SB, Majeska RJ, Schaffler MB, Martignetti JA. Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth. Hum Mol Genet. 2007 16:1113-23.

Koo, B-H., Le Goff, C., Jungers K.A., O'Flaherty, J., Weyman, C.M. and Apte S.S. ADAMTS-like 2 (ADAMTSL2) is a secreted glycoprotein that is widely expressed during mouse embryogenesis and is regulated during skeletal myogenesis. Matrix Biology, 2007 Jul;26(6):431-4

Koo, B-H., Hurskainen, T., Mielke, K., Autio-Harmainen, H., Apte S.S. ADAMTSL3/ punctin-2, a gene frequently mutated in colorectal tumors, is widely expressed in normal and malignant epithelial cells, vascular endothelial cells and other cell types and its mRNA is reduced in colon cancer. Int J Cancer, 2007, 121:1710-6.

Genis L, Gonzalo P, Tutor AS, Galvez BG, Martinez-Ruiz A, Zaragoza C, Lamas S, Tryggvason K, Apte SS , Arroyo AG. Functional interplay between endothelial nitric oxide synthase and membrane type 1-matrix metalloproteinase in migrating endothelial cells. Blood. 2007 Jul 2 (Epub)

2006

Le Goff, C., Somerville R.P.T.,, Kesteloot, F., Powell K., Birk, D., Colige, A.C., and Apte, S.S . Regulation of collagen biosynthesis by tissue-specific expression of structurally and functionally homologous ADAMTS proteases. Development , 2006 Apr;133(8):1587- 96

Koo, B-H., Longpre, J-M., Somerville, R.P.T., Alexander, J.P., Leduc, R., and Apte S.S . Cell-Surface Processing of pro-ADAMTS9 by proprotein convertases. J Biol Chem , 2006, 281(18):12485-94

2000-2005 (selected papers)

Demircan K., Hirohata, S., Niishida, K., Hatipoglu, O.F., Oohashi., T., Yonezawa, T., Apte, S.S., and Ninomiya, Y. ADAMTS-9 is synergistically induced by interleukin-1beta and tumor necrosis factor alpha in OUMS-27 chondrosarcoma cells and in human chondrocytes. Arthritis Rheum. 2005 52(5):1451-60.

Huxley-Jones, J., Apte, S.S., Robertson, D.L., Boot-Handford, R.P. The characterisation of six ADAMTS proteases in the basal chordate Ciona intestinalis provides new insights into the vertebrate ADAMTS family. Int J Biochem Cell Biol. 2005 Sep;37(9):1838-45.

Jungers K.A., Le Goff C., Somerville, R.P.T. and Apte S.S. Adamts9 is widely expressed during mouse development. Gene Expression Patterns (Mech Dev) 2005, 5:609-17

Oblander SA, Zhou Z, Galvez BG, Starcher B, Shannon JM, Durbeej M, Arroyo AG, Tryggvason K, ApteSS . Distinctive functions of membrane type 1 matrix- metalloprotease (MT1-MMP or MMP-14) in lung and submandibular gland development are independent of its role in pro-MMP-2 activation. Dev Biol. 2005 ;277:255-69.

Somerville R P T, Longpre JM, Apel ED, Lewis RM, Wang LW, Sanes J, Leduc R, Apte SS. ADAMTS7B, the full-length product of the ADAMTS7 gene, is a chondroitin sulphate- proteoglycan containing a mucin domain. J Biol Chem. 2004 279; 35159-35175

Somerville RP, Jungers KA, Apte SS . Discovery and characterization of a novel, widely expressed metalloprotease, ADAMTS10, and its proteolytic activation. J Biol Chem. 2004 3;279:51208-17

Apte SS. A disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motifs: the ADAMTS family. Int J Biochem Cell Biol 36:981-985, 2004.

Somerville R, Longpre JM, Engle JM, Ross M, Evanko S, Wight TN, Leduc R, Apte SS. Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1. J Biol Chem 278:9503-9513, 2003.

Somerville R, Oblander S, Apte SS. Matrix metalloproteinases; old dogs with new tricks. Genome Biol 4:216, 2003.

Rao C, Foernzler D, Loftus SK, Liu S, McPherson JD, Jungers KA, Apte SS, Pavan WJ, Beier DR. A defect in a novel ADAMTS family member is the cause of the belted white- spotting mutation. Development 130:4665-4672, 2003.

Hall NG, Klenotic P, Anand-Apte B, Apte SS. ADAMTSL-3/punctin-2, a novel glycoprotein in extracellular matrix related to the ADAMTS family of metalloproteases. Matrix Biol 22:501-510, 2003.

Hirohata S, Wang W, Miyagi M, Yang L, Seldin MF, Keen DR, Crabb JR, Apte SS. Punctin, a noval ADAMTS-like molecule (ADAMTSL-1) in extracellular matrix. J Biol Chem 277:12182-12189, 2002.

Fernandes RJ, Hirohata H, Engle JM, Colige A, Cohn DH, Eyre DR, Apte SS. Procollagen II amino-propeptide processing by ADAMTS-3: insights on dermatosparaxis. J Biol Chem 276:31502-31509, 2001.

Zhou Z, Apte SS, Wang J, Rauser R, Baaklini G, Soininen R, Tryggvason K. Defective skeletal growth, angiogenesis and premature death in MMP-14 deficient mice. Proc Natl Acad Sci USA 97:4052-4057, 2000.

Prior to 2000 (Significant Papers)

Hurskainen TL, Hirohata S, Seldin MF, Apte SS. ADAM-TS5, ADAM-TS6 and ADAM- TS7, novel members of a new family of zinc metalloproteases (ADAM-TS, A Disintegrin And Metalloprotease domain with ThromboSpondin type I motifs). General features and genomic distribution of the ADAM-TS family . J Biol Chem 274:25555-25563 , 1999.

Apte SS, Fukai N, Beier DR, Olsen BR. The matrix metalloproteinase-14 (MMP-14) gene is structurally distinct from other MMP genes and is co-expressed with the TIMP 2 gene during mouse embryogenesis. J Biol Chem 272:25511-25517, 1997.

Apte SS, Olsen BR, Murphy G. The gene structure of tissue inhibitor of metalloproteinases-3 (TIMP-3) and its inhibitory activities define the distinct TIMP family. J Biol Chem 270:14313-14318, 1995.

Apte SS, Mattei MG, Olsen BR. Cloning of cDNA encoding human tissue inhibitor of metalloproteinases-3 (TIMP-3) and mapping of the TIMP3 gene to chromosome 22. Genomics 19:86-90, 1994.

Apte, S.S ., Kenwright J., " Physeal distraction and cell proliferation in the growth plate". J. Bone Joint Surg. 1994; 76-B: 837-43.

Apte, S.S ., Mattei, M-G, Olsen, B.R., "Cloning of human a1(X) collagen DNA and localization of the COL10A1 gene to the q21-q22 region of human chromosome 6", FEBS Lett. 1991; 282: 393-396.

Apte, S.S ., "Validation of the use of bromodeoxyuridine immunohistochemistry for localization of S-phase cells in decalcified tissues. A comparative study with tritiated thymidine autoradiography", Histochemical Journal 1990; 22:401-408.

Extracellular matrix degradation plays a key role in skeletal growth and arthritis. Many of our past and present studies focus on the growth plate (left) and articular cartilage (right).