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Search Program Faculty/Research

Andrew P. Hinck, Ph.D.



The research in the Hinck laboratory is focused on the proteins of the transforming growth factor beta (TGF-b) superfamily - these are small secreted signaling proteins that are responsible for regulating a vast array of eukaryotic cell biology, from establishment the overall body plan during embryogenesis, to regulation of cell growth and differentiation. 

The importance of the proteins of the superfamily is demonstrated by the many human diseases that result from disruption or dysregulation of signaling, including cancer and fibrosis caused by aberrant TGF-b signaling and fibrodysplasia ossificans progressiva (FOP) caused by aberrant bone morphogenetic protein (BMP) signaling.

The focus of research underway in the Hinck laboratory is to identify the molecular adaptations that have evolved to enable factors of the superfamily to induce their specific responses – the focus of much of this work has been on the adaptations that restrict binding of a specific subset of ligands (e.g. the TGF-bs) to specific receptors (e.g. the TGF-b type I and type II receptors, or as they are also known, TbRI and TbRII). To accomplish this, NMR spectroscopy, as well as other structural (X-ray, Small Angle X-ray Scattering) and biophysical methods (Analytical Ultracentrifugation, Surface Plasmon Resonance, Microcalorimetry, etc) are being used to define assembly mechanisms for representative members of the superfamily, including the TGF-bs, BMPs, and activins. The long-term objective is to translate our structural and mechanistic insights to guide the design of therapeutic agents for treating the many human disorders and diseases caused by aberrant superfamily signaling.

The previous studies in the Hinck laboratory focused on determining the structures of the disulfide-rich TGF-bs and TGF-b receptors, TbRI and TbRII, alone and as bound to one another. These studies, along with parallel studies carried out in other laboratories on the BMPs, showed that in spite of their similar folds, the ligands and receptors of the different subfamilies bind their receptors and assemble them into complexes in ways that are entirely distinct. TGF-bs bind their receptors, TβRI and TβRII, on underside of the “fingers” and “fingertips” respectively, while the BMPs bind their type I and type II receptors on the “wrist” and “knuckles” respectively. 

The structures of the receptor complexes, together with accompanying functional studies carried out in this and other laboratories showed that the repositioning of the receptors is driven by relatively minor, but important changes in the loop regions of the receptors. Taken together, these structural and functional studies demonstrated how the proteins and the receptors of the superfamily have co-evolved alternative binding modes. These alternative binding modes increase the range of specificity and are responsible for segregating the actions of the TGF-bs and activins, evolutionary latecomers to the superfamily that activate Smads 2 and 3, from the BMPs and GDFs, the ancestors that activate Smads 1, 5, and 8.

The present studies in the laboratory are focused in two distinct areas. The first area is to continue NMR and X-ray based structural studies to identify the molecular adaptations that have evolved to enable factors of the superfamily to induce their specific responses. The first structural project is focused on understanding how the evolutionary intermediate, activin A, binds and assembles its type I and type II receptors into a signaling complex. This project is of interest, as this will provide insights as to whether the differences in type I and type II receptor binding for the TGF-bs compared to the BMPs arose in a stepwise or concerted manner. The second structural project is focused on understanding the how the co-receptors, betaglycan and endoglin, potentiate receptor complex assembly and signaling for TGF-b2 and BMP-9, respectively. This project is of interest, as it will provide insights as to the mechanism by which these accessory binding proteins selectively recognize these TGF-b family ligands and thus provide a means of targeting them to cells and tissues where these co-receptors are expressed.

The second area is to exploit the differences in the architectures of the TGF-b and BMP receptor signaling complexes that our structural studies uncovered to develop highly potent TGF-b inhibitors for treatment of cancer or fibrosis. There are two distinct avenues we are pursuing to develop novel inhibitors. The first involves artificially fusing together the binding domains of the TGF-b receptors (TbRI, TbRII, and betaglycan) to form hetero-dimeric, -trimeric, and –tetrameric sequestering proteins with high intrinsic specificity and affinity for the TGF-b isoforms. The other approach involves a combination of fluorescence TR-FRET based high throughput screening and NMR based fragment screening to identify small molecules that bind to TGF-b or the TGF-b receptors and block assembly of the TGF-b signaling complex. The advantage of this approach for inhibiting TGF-b compared with other types of small molecule inhibitors, such as TbRI and TbRII kinase inhibitors, is increased specificity since they target the TGF-b receptor complex, which is distinct compared to other proteins of the superfamily.

Some of the most significant research and review articles that have come out of the lab in the past several years are as follows:

Selected Publications:

Huang, T., Schor, S. L., Hinck, A. P., (2014) “Biological activity differences between TGF-b1 and TGF-b3 correlate with differences in the rigidity and arrangement of their component monomersBiochemistry, 53, 5737-5749. PMID: 25204799

Mahlawat, P, Ilangovan, U., Biswas, T., Sun, L-Z., Hinck, A. P. (2012) “Structure of the Alk1 extracellular domain and characterization of its BMP binding propertiesBiochemistry, 51, 6328-6341. PMID: 22799562

Hinck, A. P. (2012) “Structural studies of the TGFbs and their receptors – insights into evolution of the TGFb superfamily," FEBS Lett, 586, 1860-1870. PMID: 22651914

Zuniga, 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. 12, 601-618 (2011). PMID: 21821041

Huang, T., David, L., Mendoza, V., Yang, Y., Villarreal, M., De, K., Sun, L., Fang, X., López-Casillas, F., Wrana, J.L., and Hinck, A. P. (2011) “TGF-b signaling is mediated by two autonomously functioning TbRI:TbRII pairs,” EMBO J., 30, 1263-1276. PMID: 21423151.

Radaev, S., Zou, Z., Huang, T., Lafer, E. M., Hinck A.P., Sun, P. D. (2010) Ternary complex of TGF-b1 reveals isoform-specific ligand recognition and receptor recruitment in the superfamily J. Biol. Chem, 285, 14806-14814. PMID: 20207738

Groppe, J., Hinck, C. S., Samavarchi-Tehrani, P., Zubieta, C., Schuermann, J., Taylor, A., Schwarz, P., Wrana, J., & Hinck, A. P. (2008) “Cooperative Assembly of TGF-b Superfamily Signaling Complexes is Mediated by Two Disparate Mechanisms and Distinct Modes of Receptor Binding,” Mol. Cell, 29, 157-168. PMID: 18243111

See also the preview by J. Massagué entitled “A very private TGF-b receptor embrace” (Mol. Cell, 29, 149-150) and research highlight by N. Gough in Science STKE (Science Signalling, 1, 46). PMID: 18243107



Ph.D., Biochemistry, University of Wisconsin, 1993

BS, Chemistry, University of Puget Sound, 1987



Phone: (210) 567-8780

Research Profile
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Graduate Students

Sun Kyung (Kate) Kim
IBMS/Molecular Biophysics & Biochemistry (Ph.D.)

Lindsey Myers
IMGP/ Cellular & Structural Biology (Ph.D.)