Jay Groppe, PhD

Biography

Education and Post-Graduate Training

• Postdoctoral Fellowship, Developmental Biology, Protein Chemistry, University of Basel, Switzerland (1993-1999)
• Postdoctoral Fellowship, Bioorganic Chemistry, University of California at Santa Barbara (1992-1993)
• Ph.D., Biochemistry - Molecular Biology, University of California at Santa Barbara, Interdepartmental Chemistry-Biology (1991)
• B.A., Biochemistry - Molecular Biology, University of California at Santa Barbara (1980)

Career History

• Associate Professor, with tenure, Department of Biomedical Sciences, Texas A&M University College of Dentistry (2013-present)
• Associate Professor, Department of Biomedical Sciences, Texas A&M University College of Dentistry (2007-2013)
• Assistant Professor/Research, Department of Biochemistry, University of Texas Health Science Center at San Antonio (2003-2007)
• Visiting Scientist, Structural Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA (2000-2003)
• Postdoctoral Scientist, Department of Cell Biology, Biozentrum, University of Basel, Switzerland (1993-1999)
• Postdoctoral Scientist, Department of Chemistry, University of California at Santa Barbara (1992-1993)
• Lecturer, Upper Division General Biochemistry, Department of Biological Sciences, University of California at Santa Barbara (Jan-Apr, 1987)

Honors and Awards

• 2012 Distinguished Teaching Award Nominee (D1 courses, by department chair)
• 2012 Baylor College of Dentistry Teacher of the Year Nominee & Finalist (by students, alumni)
• 2013 Baylor College of Dentistry Teacher of the Year Nominee & Finalist (by students, alumni)
• 2015 Baylor College of Dentistry Teacher of the Year Nominee & Finalist (by students, alumni)
• 2016 Baylor College of Dentistry Teacher of the Year; Dentistry Insider TotY 2016
  • (ineligible for nomination for subsequent 5 years > 2021)

Teaching Interests

• Teaching responsibilities include:
  • Cell and Molecular Biology of Craniofacial Tissues I (Membranes, Signal Transduction; Biomedical Sciences graduate course OBIO 640)

Research Interests

Over the last two decades, Dr. Groppe (pronounced GRAWP-ee) has focused on the structure and function of components of the Bone Morphogenetic Protein (BMP) signal transduction pathway, which plays fundamental roles throughout embryonic development, including skeletogenesis of axial, appendicular and craniofacial structures as well as dentition. Initiated as an independent direction in the laboratory of Markus Affolter at the Biozentrum (Basel, Switzerland), the work spawned a collaboration with Senyon Choe, and as a visiting scientist in the Structural Biology Laboratory at the Salk Institute for Biological Studies (La Jolla, California), culminated in determination of crystal structures of BMP-7 trapped by the cystine knot antagonist Noggin (middle right) and complexed with the extracellular domain (one pair/ligand homodimer) of a type II BMP receptor (below right). 

A second major front in the study of the inhibition of BMP signaling has emerged through collaboration with Frederick Kaplan and Eileen Shore (University of Pennsylvania School of Medicine) who identified a highly conserved gain-of-function mutation in one of four BMP receptor kinases (ALK2) as the source of a severely disabling childhood disorder, Fibrodysplasia Ossificans Progressiva or FOP. Based on a highly reliable structure-based homology model derived from the crystal structure of the TGF-β receptor kinase (ALK5), the common histidine for arginine substitution was hypothesized to further perturb the metastable regulatory region of the BMP receptor kinase, consistent with ligand-independent activation of the receptor in FOP.             

[See TAMU COD Newsletter Story on Drug Development Project, 16. Sept 2019]

Co-crystal structures of ALK2 kinase proteins in complex with small molecule ATP-competitive inhibitors determined by a group at the Structural Genomics Consortium Oxford have confirmed the homology model and allowed for structure-activity relationship (SAR) studies of lead compounds and derivatives. However, despite potency and selectivity, ATP-competitive inhibitors from efforts at Oxford as well as Harvard and Vanderbilt (C. Hong) possess off-target effects that pose a challenge to translation to the clinic and eventual bedside. As a result of our in vitro comparisons of the functions and properties of wildtype, FOP mutant, aspartate-substituted variant (constitutively activated, caALK2) and regulatory subdomain-truncated forms of the receptor kinase with over-expressed recombinant proteins purified to near homogeneity, an alternative, mechanistically novel means of inhibition has been revealed. Through the newly opened avenue, the current focus is on development of a specific therapeutic targeting the dysregulated receptor kinase, which was recently found causative of non-resectable pediatric gliomas, a second severe childhood genetic disease. Thus the need for an ALK2-specific inhibitor has become more important than ever.

Recent Grants

1. Structural Basis of ACVR1 Dysregulation in Fibrodysplasia Ossificans Progressiva; The Center for Research in Fibrodysplasia Ossificans Progressiva and Related Disorders; University of Pennsylvania School of Medicine; 12/01/06-11/30/13. (PI)
2. Mechanisms of BMP Receptor Kinase Dysregulation in Skeletal Dysplasis. NIH/NIAMS R03 (1R03 AR056838-01); 12/15/08-11/30/12. (PI)
3. Novel Allosteric Inhibitors of ALK2 Receptor Kinase. The Center for Research in Fibrodysplasia Ossificans Progressiva and Related Disorders; University of Pennsylvania School of Medicine; 06?01/15-05/31/17 (PI)
4. H-SAAD/Ds: Hypoxia-Selective ALK2 Allosteric Destabilizers & Degraders for FOP Prophylaxis. International Fibrodysplasia Ossificans Progressiva Association; 12/01/17-11/30/18 (PI)

Selected Publications

1. Ferguson, J., Groppe, J.C., and Reed, S.I. (1981).  Construction and characterization of three yeast-Escherichia coli shuttle vectors designed for rapid subcloning of yeast genes on small DNA fragments. Gene16:191-197.   
2. Reed, S.I., Ferguson, J., and Groppe, J.C.  (1982).  Preliminary characterization of the transcriptional and translational products of the Saccharomyces cerevisiae cell division cycle gene CDC 28.Mol Cell Biol 2:412-425.  
3. Groppe, J.C., and Morse, D.E. (1993).  Isolation of full-length RNA templates for reverse transcription from tissues rich in RNase and proteoglycans.Anal Biochem 210:337-343.   
4. Groppe, J.C., and Morse, D.E. (1993).  Molluscan chymotrypsin-like protease: Structure, localization and substrate specificity.Arch Biochem Biophys 305:159-169.   
5. Hansma, H.G., Sinsheimer, R.L., Groppe, J., Bruice, T.C., Elings, V., Gurley, Gl., Bezanilla, M., Mastrangelo, I.A., Hough, P.V.C., and Hansma, P.K. (1993).  Recent advances in atomic force microscopy of DNA. Scanning 15:296-299.   
6. He, G.-X., Browne, K.A., Groppe, J.C., Blasko, A., Mei, H-Y., and Bruice, T.C. (1993).  Microgonatropens and their interactions with DNA.  I. Synthesis of the tri-pyrrole peptides dienmicrogonatropen-a,-b,-c and characterization of their interactions with dsDNA.J Am Chem Soc 115:7061-7071.
7. Bregnant, T.M., Groppe, J., and Little, R.D. (1994).  New class of DNA-cleaving agents based on trimethylenemethane.  J Am Chem Soc116:3635-3636.   
8. Affolter, M., Montagne, J., Walldorf, U., Groppe, J., Kloter, U., LaRosa, M., and Gehring, W.J. (1994).  The Drosophila SRF homolog is expressed in a subset of tracheal cells and maps within a genomic region required for tracheal development.Development 120:743-753.   
9. Groppe, J.C., and Morse, D.E. (1995).  Sequence-independent detection of gene family homologs: Identification of a transcript encoding a molluscan serine protease homologous to the pancreatic enzymes of vertebrates. Comp Biochem Physiol 110B:75-82. 
10. Degnan, B.M., Groppe, J.C., and Morse, D.E. (1995).  Chymotrypsin mRNA expression in digestive gland amoebocytes: Cell specification occurs prior to metamorphosis and gut morphogenesis in the gastropod, Haliotis rufescens.  Roux's Arch Dev Biol 205:97-101.   
11. Guillemin, K., Groppe, J., Ducker, K., Treisman, R., Hafen, E., Affolter, M., and Krasnow, M.A. (1996).  The pruned gene encodes the Drosophila serum response factor and regulates cytoplasmic outgrowth during terminal branching of the tracheal system.Development 122:1353-1362.   
12. Montagne, J., Groppe, J., Guillemin, K., Krasnow, M.A., Gehring, W.J., and Affolter, M. (1996). The Drosophila serum response factor gene is required for the formation of intervein tissue of the wing and is allelic to blistered. Development122:2589-2597.  
13. Groppe, J., Rumpel, K., Economides, A.N., Stahl, N., Sebald, W., and Affolter, M.  (1998). Biochemical and biophysical characterization of refolded Drosophila DPP, a homolog of bone morphogenetic proteins 2 and 4.J Biol Chem 273:29052-29065.   
14. Nussbaumer, J., Halder, G., Groppe, J., Affolter, M., and Montagne, J. (2000).  Expression of the blistered/DSRF gene is controlled by different morphogens during Drosophila trachea and wing development.Mech Dev 96:27-36.   
15. Perrin, M.H., Fischer, W.H., Kunitake, K.S., Craig, A.G., Koerber, S.C., Cervini, L.A., Rivier, J.E., Groppe, J.C., Greenwald, J., Nielsen, S.M., and Vale, W.W. (2001).  Expression, purification, and characterization of a soluble form of the first extracellular domain of the human type 1 corticotropin releasing factor receptor. J Biol Chem 276:31528-31534.   
16. Groppe, J., Greenwald., J., Wiater, E., Rodriguez-Leon, J., Economides, A., Kwiatkowski, W., Affolter, M., Vale, W.W., Izpisua-Belmont, J.C., and Choe, S. (2002).  Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature 420:636-642.

Commented on by:

Wrana, J. (2002). Structural biology: On the wings of inhibition.  Nature 420:613-614.

Highlighted by:

UCSD/Nature Signaling Gateway (Dec 2002).  BMP signal inhibition by Noggin: The shape of things to come, online.

17. Greenwald, J.,Groppe, J., Gray, P., Wiater, E., Kwiatkowski, W., Vale, W.W., and Choe, S. (2003).  The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Mol Cell 11:605-617.

Commented on by:

Sebald, W., and Mueller, T.D. (2002). The interaction of BMP-7 and ActRll implicates a new mode of receptor assembly.  Trends Biochem Sci 28:518-521

Sun, P.D. (2003).  Conserved in structure but diverse in recognition.  Structure 11:362-363.

18. Groppe, J., Greenwald, J. Wiater, E., Rodriguez-Leon, J., Economides, A., Kwiatkowski., W. Baban, K., Affolter, M., Vale, W.W., Izpisúa-Belmonte, J.C., and Choe, S. (2003).  Structural basis of BMP signaling inhibition by Noggin, a novel twelve-membered cystine knot protein.J Bone Joint Surg Am 85-A, Supplement 3: 52-58.
19. Ilangovan, J., Ding, W., Zhong, Y., Wilson, C.L., Groppe, J.C., Trbovich, J.T., Zúñiga, J., Demeler, B., Tang, Q., Gao, L., Mulder, K.M., and Hinck, A.P. (2005).  Structure and dynamics of the homodimeric dynein light chain km23.J Mol Biol 352:338-354.   
20. Zúñiga, J.E., *Groppe, J.C., Cui, Y., Hinck, C.S., Contreras-Shannon, V., Pakhomova, O.N., Yang, J., Tang, Y., Mendoza, V., López-Casillas, F., Sun, L.-Z., and Hinck, A.P. (2005).  Assembly of TβRI:TβRII:TGFβ ternary complex in vitro with receptor extracellular domains is cooperative and isoform-dependent.J Mol Biol 354:1052-1068  (*equal first author, wrote paper).   
21. Groppe, J.C., Shore, E.M., and Kaplan, F.S. (2007).  Functional modeling of the ACVR1 (R206H) mutation in FOP.Clin Orthop Relat Res 462:87-92.   
22. Kaplan, F.S., Groppe, J., Pignolo, R.J., and Shore, E.M. (2007).  Morphogen receptor genes and metamorphogenes: Skeleton keys to metamorphosis.Ann NY Acad Sci 1116:113-133.
23. Groppe, J., Hinck, C.S., Samavarchi-Tehrani, P., Zubieta, C., Schuermann, J.P., Taylor, A.B., Schwarz, P.M., Wrana, J.L., and Hinck, A.P. (2008). Cooperative assembly of TGF-β superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol Cell 29:157-168

Commented on by:

Massagué, J. (2008). A very private TGF-β receptor embrace. Mol Cell 29:149-150.

Gough, N.R. (2008).  Monogamy in the TGF-β receptor relationship.  Science Signaling Vol 1 (5):46.

Montoya, M., (2008).  Signaling distinctions.  Nat Struct Mol Biol 15:227.

24. Kaplan, F.S., Le Merrer, M., Glaser, D.L., Pignolo, R.J., Goldsby, R.E., Kitterman, J.A., Groppe, J., and Shore, E.M. (2008).  Fibrodysplasia ossificans progressiva.Best Pract Res Clin Rheumatol 22:191-205.
25. Kaplan, F.S., Shen, Q., Lounev, V., Seeman, P., Groppe J., Katagiri T., Pignolo, R.J., and Shore, E.M. (2008). Skeletal metamorphosis in Fibrodysplasia Ossificans Progressiva (FOP).  J Bone Miner Res26:521-530.
26. Kaplan, F.S., Groppe, J., and Shore, E.M. (2008).  When one skeleton is enough: Approaches and strategies for the treatment of fibrodysplasia ossificans progressiva (FOP). Drug DiscovToday Ther Strateg 5:255-262.
27. Kaplan, F.S., Xu, M., Seemann, P., Connor, M., Glaser, D.L., Carroll, L., Delai, P., Fastnacht-Urban, E., Forman, S.J., Gillessen-Kaesbach, G., Hoover-Fong, J., Köster, B., Pauli, R.M., Reardon, W., Zaidi, S.-A., Zasloff, M., Morhart, R., Mundlos, S., Groppe, J., and Shore, E.M. (2009).  Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat 30:379-90.
28. Wang, Y., Groppe, J.C., Wu, J., Ogawa, T., Mues, G., D'Souza, R.N., and Kapadia, H. (2009).  Pathogenic mechanisms of tooth agenesis linked to paired domain mutations in human PAX9.Hum Mol Genet 18:2863-2874.
29. Nickel, J., Sebald, W., Groppe, J.C., and Mueller, T.D. (2009). Intricacies of BMP receptor assembly.Cytokine Growth Factor Rev 20:367-77.
30. Seemann, P., Brehm, A., König, J., Reissner, C., Stricker, S., Kuss, P., Haupt ,J., Renninger, S., Nickel, J., Sebald, W., Groppe, J.C., Plöger, F., Pohl, J., Schmidt-von Kegler, M., Walther, M., Gassner, I., Rusu, C., Janecke, A.R., Dathe, K., and Mundlos, S. (2009). Mutations in GDF5 reveal a key residue mediating BMP inhibition by NOGGIN.PloS Genet 5:e1000747. 
31. Kaplan, F.S., Groppe, J., Seeman, P., Pignolo, R.J., and Shore, E.M. (2010).  Fibrodysplasia ossificans progressiva: Developmental implications of a novel metamorphogene.  Bone and Development(Vol. 6). Topics in Bone Biology, Chapter 14.  Bronner, Farach-Carson and Roach, editors.
32. Kuhfahl, S., Hauburger, A., Thieme, T., Groppe, J., Ihling, C., Tomic, S., Schutkowski, M., Sinz, A., and Schwarz, E. (2011).  Identification of a core domain within the proregion of bone morphogenetic proteins that interacts with the mature, dimeric domain.  Biochem Biophys Res Commun408:300-305.
33. Groppe, J., Wu, J., Shore, E.M., and Kaplan, F.S. (2011). In vitro analysis of the dysregulated R206H ALK2 Kinase-FKBP12 interaction associated with heterotopic ossification in FOP.  Cells Tissues Organs 194:291-295.
34. Zúñiga, J.E., Ilangovan, U., Mahlawat, P., Hinck, C.S., Huang, T., Groppe, J.C., McEwen, D.G., and Hinck, A.P. (2011).  The TβR-I pre-helix extension is structurally ordered in the unbound form and its flanking prolines are essential for binding J Mol Biol 412:601-618.
35. Ishii, Y., Takizawa, T., Iwasaki, H., Fujita, Y., Murakami, M., Groppe, J.C., and Tanaka, K. (2012).  Nucleotide polymorphisms in the canine Noggin (NOG) gene and their distribution among dog (Canis lupus familiaris) breeds. Biochem Genet 50:12-18.
36. Zimmer, J., Doelken, S., Horn, D., Groppe, J.,Shore, E., Kaplan, F., and Seemann, P. (2012).  Functional analysis of alleged NOGGIN mutation G92E disproves its pathogenic relevance.  PLoS ONE 7(4): e35062.
37. Wang, X., Wang, S., Li, C., Gao, T., Liu, Y., Rangiani, A., Sun, Y., Hao, J., George, A., Lu, Y., Groppe, J., Yuan, B., Feng, J., and Qin C. (2012).  Inactivation of a novel FGF23 regulator, FAM20C, leads to hypophosphatemic rickets in mice.  PLoS Genetics 8(5): e1002708.
38. Whitman, M., Rosen, V., Brivanlou, A.H., Groppe, J.C., Sebald, W., and Mueller, T. (2013).  Regarding the mechanism of action of a proposed peptide agonist of the bone morphogenetic protein receptor activin-like kinase 3.  Nat Med19:809-810.
39. Kaplan, F.S., Kobori, J.A., Orellana, C., Calvo, I., Rosello, M., Martinez, F., Lopez, B., Xu, M., Pignolo, R.J., Shore, E.M., and Groppe, J.C. (2015). Multi-System Involvement in a Severe Variant of Fibrodysplasia Ossificans Progressiva (ACVR1 c. 772G>A; R258G): A Report of Two Patients. Am J Med Genet A 167A(10):2265-71.
40. Wang, H., Lindborg, C., Lounev, V., Kim, J.H., McCarrick-Walmsley, R., Xu, M., Mangiavini, L., Groppe, J.C., Shore, E.M., Schipani, E., Kaplan, F.S., Pignolo, R.J. (2016).  Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling. J Bone Miner Res 31 (9):1652-65.  
41. Lu, G., Tandang-Silvas, M.R., Dawson, A.C., Dawson, T.J., Groppe, J.C. (2018). Hypoxia-selective allosteric destabilization of activin receptor-like kinases: A potential therapeutic avenue for prophylaxis of heterotopic ossification. Bone 112:71-89. 
42. Groppe, J.C. (2019). Induced degradation of protein kinases by bifunctional small molecules: a next-generation strategy. Expert Opin Drug Discov 12:1-17. 
43. Kaplan, F.S., Groppe, J.C., Xu, M., Towler, O.W., Grunvald, E., Kalunian, K., Kallish, S., Al Mukaddam, M., Pignolo, R.J., Shore, E.M. (2022). An ACVR1^R375P pathogenic variant in two families with mild fibrodysplasia ossificans progressiva. Am J Med Genet A. 188:806-817.
44. Wentworth, K.L., Lalonde, R.L., Groppe, J.C., Brewer, N., Moody, T., Hansberry, S., Taylor, K.E., Shore, E.M., Kaplan, F.S., Pignolo, R.J., Yelick, P.C., Hsiao, E.C. (2022). Functional Testing of Bone Morphogenetic Protein (BMP) Pathway Variants Identified on Whole-Exome Sequencing in a Patient with Delayed-Onset Fibrodysplasia Ossificans Progressiva (FOP) Using ACVR1^R206H -Specific Human Cellular and Zebrafish Models. J Bone Miner Res. 37:2058-2076.

45. Groppe, J.C., Lu, G., Tandang-Silvas, M.R., Pathi, A., Konda, S., Wu, J., Le, V.Q., Culbert, A., Shore, E.M., Wharton, K.A., Kaplan, F.S. (2023). Polypeptide Substrate Accessibility Hypothesis: Gain-of-Function R206H Mutation Allosterically Affects Activin Receptor-like Protein Kinase Activity. Biomolecules 13(7):1129; https://doi.org/10.3390/biom13071129 

    (This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva (FOP): From Molecular Mechanisms to Therapeutic Strategies)

46.  Lounev, V., Groppe, J.C., Brewer, N., Wentworth, K.L., Smith, V., Xu, M., Schomburg, L., Bhargava, P., Al Mukaddam, M, Hsiao, E.C., Shore, E.M., Pignolo, R.J., Kaplan, F.S. (2024). Matrix metalloproteinase-9 deficiency confers resilience in fibrodysplasia ossificans progressiva in a man and mice. J. Bone Miner Res 39(4):382-398.
    Commented on by: Wein, M.N. and Yang, Y. (2024).  Actionable disease insights from bedside-to-bench investigation in fibrodysplasia ossificans progressiva. J. Bone Miner Res 39(4):375-376.