Suneel S. Apte,  M.B.B.S., D.Phil.

Suneel S. Apte, M.B.B.S., D.Phil.

Staff

Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio 44195
Location: ND2-29
Email: aptes@ccf.org
Phone: (216) 445-3278
Fax: (216) 444-9198

Apte Laboratory

 

INTEGRATED BIOLOGY of EXTRACELLULAR MATRIX, CELLS and PROTEASES in MORPHOGENESIS and HUMAN DISORDERS Extracellular matrix (ECM)is the inanimate material that surrounds cells and provides a scaffold for tissue and organ architecture. Although inanimate, it is not static and undergoes constant remodeling by proteases. We undertake fundamental research on ECM and proteases and apply it to a variety of diseases. A specific class of proteases, the ADAMTS proteases, is a major focus of this laboratory, which studies their intrinsic properties, biological mechanisms and roles in human disease. We investigate how their mutations cause birth defects affecting the heart, blood vessels, neural tube, eyes, palate and limbs. Our research is also relevant to maternal-fetal health and inherited human connective tissue disorders such as Marfan syndrome and the acromelic dysplasias. We investigate acquired human disorders such as aortic aneurysms, osteoarthritis, cancer and cardiac failure. The technologies employed in the laboratory include biochemistry, cell biology, and genetics. The laboratory makes extensive use of proteomics to identify protease substrates and define the proteolytic landscape of diseased human tissues.

Please click on the publications tab at the top of this page for earlier publications or visit Dr. Apte's profile on Google Scholar and at http://www.ncbi.nlm.nih.gov/pubmed/


Publications (2020)

Martin DR, Witten JC, Tan CD, Rodrigues ER, Pettersson GB, Seifert DE, Willard BB, Apte SS. Proteomics identifies a convergent innate response to infective endocarditis and extensive proteolysis in vegetation components. JCI Insight 2020 Jun 16;135317. doi: 10.1172/jci.insight.135317

Ataca D, Aouad P, Constantin C, Laszlo C, Beleut M, Shamseddin M, Rajaram RD, Jeitziner R, Mead TJ, Caikovski M, Bucher P, Ambrosini G, Apte SS, Brisken C. The secreted protease ADAMTS18 links hormone action to activation of the mammary stem cell niche. Nat Commun. 2020 Mar 26;11(1):1571. doi: 10.1038/s41467-020-15357-y.

Evans DR, Green JS, Fahiminiya S, Majewski J, Fernandez BA, Deardorff MA, Johnson GJ, Whelan JH, Hubmacher D, Apte SS; Care4Rare Canada Consortium, Woods MO. A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand featuresSci Rep. 2020 Jul 2;10(1):10827. doi: 10.1038/s41598-020-66978-8

Apte SS. ADAMTS Proteins: Concepts, Challenges, and Prospects. Methods Mol Biol. 2020;2043:1-12. doi: 10.1007/978-1-4939-9698-8_1. Review.

Mead TJ, Apte SS.Visualization and Quantification of Pericellular Matrix. Methods Mol Biol. 2020;2043:261-264. doi: 10.1007/978-1-4939-9698-8_21.

Mead TJ, Apte SS.Expression Analysis by RNAscope™ In Situ Hybridization. Methods Mol Biol. 2020;2043:173-178. doi: 10.1007/978-1-4939-9698-8_14.

Research articles (2019)

Wang LW, Nandadasa S, Annis DS, Dubail J, Mosher DF, Willard BB, Apte SS. A disintegrin-like and metalloproteinase domain with thrombospondin type 1 motif 9 (ADAMTS9) regulates fibronectin fibrillogenesis and turnover. J Biol Chem, 2019,294:9924-9936. doi: 10.1074/jbc.RA118.006479

Hubmacher, D, Thacker, S, Adams SM,  Birk, D,  Schweitzer, R, Apte, SS. Limb- and tendon-specific   Adamtsl2   deletion identifies a soft tissue mechanism modulating bone length. Matrix Biology, 2019. pii: S0945-053X(18)30372-X. doi: 10.1016/j.matbio.2019.02.001. 

Nandadasa, S, Kraft, CM, O’Donnell, A, Wang, LW, O’Donnell, A, Patel, R, Gee HY, Grobe, K, Cox, TC, Hildebrandt F and Apte, SS. Secreted metalloproteases   ADAMTS9 and ADAMTS20 have a non-canonical role in ciliary vesicle growth   during ciliogenesis. Nature Communications, (2019) 10:953 | https://doi.org/10.1038/s41467-019-08520-7

Choi YJ, Halbritter J, Braun DA, Schueler M, Schapiro D, Rim JH, Nandadasa S, Choi WI, Widmeier E, Shril S, Körber F, Sethi SK, Lifton RP, Beck BB, Apte SS, Gee HY,Hildebrandt F. Mutations of ADAMTS9 Cause Nephronophthisis-Related Ciliopathy. Am J Hum Genet. 2019 104:45-54. doi: 10.1016/j.ajhg.2018.11.003.

Wang LW, Kutz WE, Mead TJ, Beene LC, Singh S, Jenkins MW, Reinhardt DP, Apte SS.  Adamts10 inactivation in mice leads to persistence of ocular microfibrils subsequent to reduced fibrillin-2 cleavage. Matrix Biol. 2019, 77:117-128.  pii: S0945-053X(18)30253-1. doi: 10.1016/j.matbio.2018.09.004. 

Jensen LD, Hot B, Ramsköld D, Germano RFV, Yokota C, Giatrellis S, Lauschke VM, Hubmacher D, Li MX, Hupe M, Arnold TD, Sandberg R, Frisén J, Trusohamn M, Martowicz A, Wisniewska-Kruk J, Nyqvist D, Adams RH, Apte SS, Vanhollebeke B, Stenman JM, Kele J. Disruption of the Extracellular Matrix Progressively Impairs Central Nervous System Vascular Maturation Downstream of β-Catenin Signaling. Arterioscler Thromb Vasc Biol. 2019 39:1432-1447. doi: 10.1161/ATVBAHA.119.312388. 

Santamaria S, Yamamoto K, Teraz-Orosz A, Koch C, Apte SS, de Groot R, Lane DA, Ahnström J. Exosites in Hypervariable Loops of ADAMTS Spacer Domains control Substrate Recognition and Proteolysis. Sci Rep. 2019 Jul 29;9(1):10914. doi: 10.1038/s41598-019-47494-w

Holdener BC, Percival CJ, Grady RC, Cameron DC, Berardinelli SJ, Zhang A, Neupane S, Takeuchi M, Jimenez-Vega JC, Uddin SMZ, Komatsu DE, Honkanen R, Dubail J, Apte SS, Sato T, Narimatsu H, McClain SA, Haltiwanger RS. ADAMTS9 and ADAMTS20 are differentially affected by loss of B3GLCT in a mouse model of Peters Plus Syndrome.  Hum Mol Genet. 2019 Oct 10. pii: ddz225. doi: 10.1093/hmg/ddz225. [Epub ahead of print]

Graae AS, Grarup N, Ribel-Madsen R, Lystbæk SH, Boesgaard T, Staiger H, Fritsche A, Wellner N, Sulek K, Kjolby M, Backe MB, Chubanava S, Prats C, Serup AK, Birk JB, Dubail J, Gillberg L, Vienberg SG, Nykjær A, Kiens B, Wojtaszewski JFP, Larsen S, Apte SS, Häring HU, Vaag A, Zethelius B, Pedersen O, Treebak JT, Hansen T, Holst B.ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations. Diabetes. 68(3):502-514. doi: 10.2337/db18-0418.

Research articles (2018)

Mead TJ, Du Y, Nelson CM, Gueye N-A, Drazba J, Dancevic CM, Vankemmelbeke M, Buttle DJ,  Apte SS. ADAMTS9-Regulated Pericellular Matrix Dynamics Governs Focal Adhesion-Dependent Smooth Muscle Differentiation. Cell Reports. 2018, 23; 2, 485-498.

Mead TJ, McCulloch DR, Ho JC, Du Y, Adams SM, Birk DE, Apte SS. The metalloproteinase-proteoglycans ADAMTS7 and ADAMTS12 provide an innate, tendon-specific protective mechanism against heterotopic ossification. JCI Insight. 2018 April5;3(7). pii: 92941. doi: 10.1172/jci.insight.92941

Cikach FS, Koch CD, Mead TJ, Galatioto J, Willard BB, Emerton KB, Eagleton MJ, Blackstone EH, Ramirez F, Roselli EE, Apte SS. Massive aggrecan and versican accumulation in thoracic aortic aneurysm and dissection. JCI Insight. 2018 Mar 8;3(5). pii: 97167. doi: 10.1172/jci.insight.97167. 

Prins, B. , Mead, T.J. (joint first authors) et al. Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. Genome Biol  2018, 19:87. https://doi.org/10.1186/s13059-018-1457-6

Schnellmann R, Sack R, Hess D, Annis DS, Mosher DF, Apte SS, Chiquet-Ehrismann R. A selective extracellular matrix proteomics approach identifies fibronectin proteolysis by ADAMTS16 and its impact on spheroid morphogenesis. Mol Cell Proteomics. 2018 Apr 18. pii: mcp.RA118.000676. doi: 10.1074/mcp.RA118.000676. [Epub ahead of print]

Aviram R, Zaffryar-Eilot S, Hubmacher D, Grunwald H, Mäki JM, Myllyharju J, Apte SS, Hasson P.  Interactions between lysyl oxidases and ADAMTS proteins suggest a novel crosstalk between two extracellular matrix families. Matrix Biol. 2018 May 11. pii: S0945-053X(17)30448-1. doi: 10.1016/j.matbio.2018.05.003. 

A sampling of research publications from 2017 and earlier:

1. Hubmacher D, Schneider M, Berardinelli S, Takeuchi H, Willard B, Reinhardt DH, Haltiwanger R, and Apte SS. Unusual life cycle and impact on microfibril assembly of ADAMTS17, a secreted metalloprotease mutated in genetic eye disease. Scientific Reports, 2017;7:41871. doi: 10.1038/srep41871.

2. Dubail, J, Vasudevan, D, Wang, LW, Earp, SE, Jenkins, MW, Haltiwanger, RS, and Apte SS. Impaired ADAMTS9 secretion: A potential mechanism for eye defects in Peters Plus Syndrome. Scientific Reports. 2016.  6:33974. doi: 10.1038/srep33974.

3. Nandadasa, S., Nelson, C.M., Apte, SS. ADAMTS9-Mediated Extracellular Matrix Dynamics Regulates Umbilical Cord Vascular Smooth Muscle Differentiation and Rotation. Cell Reports 11:1519-28,  2015

4.  Enomoto, H., Nelson, C., Somerville, R.P.T., Mielke, K., Dixon, L., Powell, K., Apte, S.S. Cooperation of two ADAMTS metalloproteases in closure of the mouse palate identifies a requirement for versican proteolysis in regulating palatal mesenchyme proliferation. Development, 2010, 37:4029-38.

5. 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. and Apte, S.S. ADAMTS metalloproteases generate active versican fragments that regulate interdigital web regression. Developmental Cell 2009, 17:687-98. PMCID:PMC2780442.

Books

Apte SS. ADAMTS proteins: Concepts, Challenges and Prospects. Methods Mol Biol. 2020;2043:1-12. doi: 10.1007/978-1-4939-9698-8_1.

Reviews, technical reports and commentaries

1. Mead TJ, Apte SS. ADAMTS proteins in human disorders.Matrix Biol. 2018 Jun 6. pii: S0945-053X(18)30179-3. doi: 10.1016/j.matbio.2018.06.002.

2. Apte, SS. Anti-ADAMTS5 monoclonal antibodies: implications for aggrecanase inhibition in osteoarthritis. Biochem J. 2016 Jan 1;473(1):e1-e4

3. Dubail J, Apte SS. Insights on ADAMTS proteases and ADAMTS-like proteins from mammalian genetics.Matrix Biol. 44-46:24-37 2015

4. Foulcer SJ, Day AJ, Apte SS. Isolation and purification of versican and analysis of versican proteolysis. Methods Mol Biol. 1229:587-604, 2015

5. Nandadasa S, Foulcer S, Apte SS. The multiple, complex roles of versican and its proteolytic turnover by ADAMTS proteases during embryogenesis. Matrix Biol. 2014, 35:34-41, 2014.

Book chapters

1. Apte, SS. Chapter 259. Connective Tissue Structure and Function. ed. Goldman L, and Shafer, A.I., Goldman-Cecil Textbook of Medicine, Twenty-Fifth Edition, Elsevier, New York, 2016, ISBN 9781455750177

2. Apte SS. ADAMTS proteases: Mediators of physiological and pathogenic extracellular proteolysis, in Bradshaw, R., and Stahl, P, eds, Encyclopedia of Cell Biology, Elsevier, New York, 2015, ISBN 9780123944474

3. Apte, SS. Chapter 2. Overview of the ADAMTS superfamily, in Rodgers, G., ed, ADAMTS13: Biology and Disease, Springer, New York, 2015, ISBN 9783319087160

4. Traboulsi I, and Apte SS. Chapter 43. Ectopia Lentis and Associated Systemic Disease, in Traboulsi, I., ed, Genetic Diseases of the Eye, Second Edition, Oxford University Press, USA, 2012, ISBN 9780195326147

Additional publications from our laboratory are obtainable from Dr. Apte's profile on Google Scholar and at http://www.ncbi.nlm.nih.gov/pubmed/


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

03/27/2019 |  

The Unexpected Role of Secreted Proteases in Birth Defects

A group of Cleveland Clinic researchers have identified how the proteases ADAMTS9 and ADAMTS20 contribute to embryonic development and how defects in these enzymes lead to serious birth defects.




08/10/2018 |  

Rare Gene Variants Related to Cardiac Dysfunction Identified

An international team of researchers, including scientists from Lerner Research Institute, has uncovered new loci (chromosomal regions) associated with heart function and development.




04/24/2018 |  

Smooth Delivery: ADAMTS9 Enhances Uterine Smooth Muscle Contractions

Rates of fetal and maternal morbidity and mortality in the United States are on the rise. A new Cleveland Clinic study shows how abnormal accumulation of extracellular matrix (ECM) prevents smooth muscle cells (SMCs) in the uterus from properly contracting, which can cause prolonged or arrested delivery and lead to poor health outcomes.