Molecular Biology; Signal Transduction; Hemangioma, Cavernous, Central Nervous System
Cerebral Cavernous Malformations (CCM)
Rho GTPase signaling cascades
Rho family GTPases are critical regulators of actin dynamics and are important for cell proliferation, apoptosis, cell-cycle and cell adhesion. We are interested in understanding the structural biology of the signaling cascades which are regulated by Rho GTPases and the ways that these pathways are altered in disease, especially cancer. We are interested in understanding how signaling by the Rho-family member, RAC1, is altered by acquisition of a point mutation at codon 29 in melanoma. We are also interested in understanding the regulation mechanisms for downstream Rho-family effector molecules, and discovered that the type II p21-activated kinases are regulated by pseudosubstrate autoinhibition.
Integrins are transmembrane receptors that play essential roles during development, tissue formation, hemostasis, and in response to injury and infection. We are interested in the integrin-linked kinase, pinch, parvin (IPP) complex, a hub in integrin-actin and integrin-signaling networks. The IPP complex has critical roles in anchorage-dependent cell growth and survival, cell cycle progression, epithelial to mesenchymal transition, cell motility, contractility and early development. The complex is also required for cardiac, vascular, brain, kidney, muscle, skin, platelet, chondrocyte and T cell function and plays important roles in tumor angiogenesis. We are also interested in understanding how the CCM proteins interact with and impact integrin signaling.
Specialized Terms: Structural biology of signal transduction
- Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex. Fisher OS, Deng H, Liu D, Zhang Y, Wei R, Deng Y, Zhang F, Louvi A, Turk BE, Boggon TJ, Su B. Nature Communications. 2015; 6:7937. doi:10.1038/ncomms8937
- CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation. Draheim KM, Li X, Zhang R, Fisher OS, Villari G, Boggon TJ, Calderwood DA. Journal of Cell Biology. 2015; 208 (7):987-1001.
- Identification of a major determinant for serine-threonine kinase phosphoacceptor specificity. Chen C, Ha BH, Thevenin AF, Lou HJ, Zhang R, Yip KY, Peterson JR, Gerstein M, Kim PM, Filippakopoulos P, Knapp S, Boggon TJ, Turk BE. Molecular Cell. 2014; 53(1):140-147.
- Mechanism for KRIT1 release of ICAP1-mediated suppression of integrin activation. Liu W, Draheim, Zhang R, Calderwood DA, Boggon TJ. Molecular Cell 2013; 49(4):719-29.
- Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate Ha BH, Davis MJ, Chen C, Lou HJ, Gao J, Zhang R, Krauthammer M, Halaban R, Schlessinger J, Turk BE, Boggon TJ. Proceedings of the National Academy of Sciences, U.S.A. 2012; 109(40):16107-16112
- Structural basis for the small G-protein-effector interaction of Ras-related protein 1 (Rap1) and the adaptor protein Krev interaction trapped 1 (KRIT1). Li X, Zhang R, Draheim KM, Liu W, Calderwood DA, Boggon TJ Journal of Biological Chemistry. 2012; 287(26):22317-22327
- Li X, Zhang R, Zhang H, He Y, Ji W, Min W, Boggon TJ. Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity. Journal of Biological Chemistry. 2010; 285(31):24099-24107.