Much of our current work revolves around mechanisms and functions of ADAMTS metalloproteases. These proteases interact with or proteolytically process a variety of ECM and other secreted molecules. Among these targets, the macromolecules fibrillin and versican are prominent, and functionally crucial in their own right, which has prompted us to investigate them more closely. After all, the biology of proteases is really the biology of their substrates.
A few highlights from the laboratory’s recent and ongoing work are summarized below:
Fundamental research on ADAMTS proteins: Several ECM-modifying ADAMTS proteases and the related ECM molecules named ADAMTS-like proteins were discovered or first characterized by our laboratory. We investigate their fundamental characteristics by asking: What do they look like? How are they regulated by cells? What are their interacting partners and substrates? What are the consequences of their deficiency or excess? What post-translational modifications render them fully functional?
ADAMTS proteins in birth defects: The laboratory has implicated defective ADAMTS proteolysis of versican in birth defects such as cleft palate, syndactyly, abnormal skin pigmentation, and congenital heart defects such as ventricular septal defect and Tetralogy of Fallot. New projects in the lab look at anomalies of limb and umbilical cord development, as well as mechanisms of hematopoeisis. Studies on cardiovascular and vascular defects are supported by an award from the NIH-NHLBI Program of Excellence in Glycosciences.
Inherited eye defects and development of the eye: Mutations of ADAMTS10, ADAMTS17 and ADAMTSL4 affect development of the ocular zonule, a fibrillin-rich structure that suspends the lens in the optic path. This anomaly, named ectopia lentis, is also common in Marfan syndrome. We investigate formation of the zonule and ectopia lentis with support from the NIH-NEI. A second project on eye development that is potentially related to an inherited disorder called Peters Plus syndrome, investigates how ADAMTS9 regulates development of the anterior half of the eye. This research is supported by awards from the NIH-NEI and the Knight Templar Eye Foundation (to Johanne Dubail, post-doctoral fellow).
ADAMTS substrates and networks: Versican, the large aggregating proteoglycan that is the substrate of many ADAMTS proteases is being nvestigated in our laboratory. We are studying novel strucural aspects of this molecule and its functions. Fibrillin microfibrils are extremely relevant to ADAMTS proteins, as a result of a genetic consilience revealed by mutations in fibrillin-1 and several ADAMTS proteins that lead to identical disorders. We investigate mechanisms of microfibril assembly relevant to ADAMTS proteins.
The laboratory has a constantly evolving portfolio of projects based on individual member’s interests and new findings. Some of the other topics currently pursued by the laboratory include development of extra-embryonic tissues and vascular biology of the fetal-maternal axis (supported by a grant from Sabrina’s Foundation) and musculoskeletal developmental anomalies (supported by an NIH F32 training award to Timothy Mead). We appreciate past support from the KTEF and Marfan Foundation that launched some of the laboratory’s current projects.
Inquiries regarding collaborations, fellowships, studentships or sabbaticals are welcomed and should be made to firstname.lastname@example.org
We are broadly interested in extracellular matrix (ECM), the dynamic, highly organized network of molecules produced by cells, mostly as proteins and carbohydrates, that lies between the cells to support them, provides them with an anchorage, and influences every aspect of their behavior and fate. ECM provides the structural framework on which every tissue and organ is built. It also contains a variety of information that tells cells what to do. There are almost no instructions received by cells that bypass the ECM.
ECM is constantly remodelled to allow adaptation to the body's changing circumstances. This is done by a fine balancing act that requires production and removal of judicious amounts of ECM- a nip and tuck here and there. It is important to get this right. Excess ECM breakdown can lead to tissue destruction, such as in osteoarthritis, or enable cancer cells to metastasize. Not enough ECM, and tissues become weak and break down. Too much ECM or incorrect ECM in the wrong place can lead to scarring and fibrosis, which are seriously detrimental to vital organs such as the liver, kidney, heart, bone marrow and brain.
ECM and cell-ECM interactions are relevant to every organ system and all human diseases. ECM is easy to overlook, challenging to investigate, and impossible to live without.
Our laboratory studies ECM in embryogenesis (developmental biology) and its perturbations that lead to birth defects involving the face, eye, heart and limbs. Our work is relevant to several human genetic disorders as well as to fetal-maternal health and acquired conditions such as arthritis, fibrosis, age-related macular degeneration, and diabetes. The fundamental and translational laboratory activities that span these interests use genetics, biochemistry and cell biology tools.
|US Patent||Patent Title||Issue Date||First-Named Inventor|
|6,391,610||Nucleic Acids Encoding Zinc Metalloproteases||5/21/2002||Suneel S. Apte Ph.D|
Representative past publications:
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, 133:1587-96
Wang, L.W., Dlugosz, M., Somerville, RPT., Raed, M., Haltiwanger, R.S., Apte, S.S. O-Fucosylation of thrombospondin type-1 repeats in ADAMTS-like1/punctin-1 regulates secretion: Implications for the ADAMTS superfamily. J Biol Chem, 2007;282:17024-31 (paper of the week)
McCulloch, D.R., Nelson, C.M., Dixon, L.J., Silver D.L., Wylie, J.D., Lindner, V., Sasaki, T., Cooley, M.A., Argraves, W.S., Apte, S.S (2009). ADAMTS metalloproteases generate active versican fragments that regulate interdigital web regression. Dev Cell 17(5):687-98
Enomoto, H., Nelson, C., Somerville, R.P.T., Mielke, K., Dixon, L., Powell, K., Apte, S.S. (2010) Cooperation of two ADAMTS metalloproteases in closure of the mouse palate identifies a requirement for versican proteolysis in regulating palatal mesenchyme proliferation. Development, 37(23):4029-38.
W. E. Kutz, L. W. Wang, H. L. Bader, A. K. Majors,, K.Iwata, E. I. Traboulsi, L. Y. Sakai, D. R. Keene and Apte S.S. (2010). ADAMTS10 protein interacts with fibrillin-1 and promotes its deposition in extracellular matrix of cultured fibroblasts. J Biol Chem. 286, 17156-67
Hattori N, Carrino DA, Lauer ME, Vasanji A, Wylie JD, Nelson CM, Apte S.S. (2011) Pericellular versican regulates the fibroblast-myofibroblast transition-A role for ADAMTS5. J Biol Chem. 2011 286:34298-310
Beene, LC, Wang, LW, HubmacherD, Keene DR, Reinhard DP, Annis, DS, Mosher, DF, Mecham, RP, Traboulsi, EI, and Apte S.S (2013). Non-selective assembly of fibrillin-1 and fibrillin-2 in the rodent ocular zonule and in cultured cells: Implications for Marfan syndrome. Invest Ophthal Visual Sci 2013, 54(13):8337-44
Publications in 2014:
Dubail J, Aramaki-Hattori N, Bader HL, Nelson CM, Katebi N, Matuska B, Olsen BR, Apte SS. A new Adamts9 conditional mouse allele identifies its non-redundant role in interdigital web regression. Genesis. 52:702-12
Foulcer SJ, Nelson CM, Quintero MV, Kuberan B, Larkin J, Dours-Zimmermann MT, Zimmermann DR, Apte SS. Determinants of Versican-V1 Proteoglycan Processing by the Metalloproteinase ADAMTS5. J Biol Chem 289(40):27859-73
Nandadasa S, Foulcer S, Apte SS. The multiple complex roles of versican and its proteolytic turnover by ADAMTS proteases during embryogenesis. Matrix Biol., 35:34-41
Schlage P, Egli FE, Nanni P, Wang LW, Kizhakkedathu JN, Apte SS, Auf dem Keller U. Time-resolved analysis of the matrix metalloproteinase 10 substrate degradome Mol Cell Proteomics. 13(2):580-93
Campbell VT1, Nadesan P, Ali SA, Wang CY, Whetstone H, Poon R, Wei Q, Keilty J, Proctor J, Wang LW, Apte SS, McGovern K, Alman BA, Wunder JS.Hedgehog pathway inhibition in chondrosarcoma using the Smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth. Mol Cancer Therapeutics 2014, 3:1259-69
Hubmacher D, Reinhardt D, Plesec T, Schenke-Layland K, Apte SS.
Invest Ophthalmol Vis Sci. Human eye development is characterized by coordinated expression of fibrillin isoforms2014 Nov 18. pii: IOVS-14-15453. doi: 10.1167/iovs.14-15453. [Epub ahead of print]
Foulcer SJ, Day AJ, Apte SS.Isolation and purification of versican and analysis of versican proteolysis. Methods Mol Biol. 2015;1229:587-604. doi: 10.1007/978-1-4939-1714-3_4