Molecular Biology; Signal Transduction; Hemangioma, Cavernous, Central Nervous System
The Boggon lab is interested in using structural biology approaches to help understand functional alterations that impact human disease. Specific areas of interest are briefly described below. Please also see the lab website: www.boggonlab.org
Cerebral Cavernous Malformations
Cerebral cavernous malformations (CCM) disease has a prevalence of 0.1-0.5% in the human population and is an important cause of hemorrhagic stroke. Between 10 and 50% of CCM cases are associated with inherited autosomal-dominant mutations in three genes, KRIT1 (CCM1),CCM2 and CCM3 (PDCD10). These mutations result in loss-of-function of the protein products of these genes (KRIT1, CCM2 and CCM3) and result in destabilized vascular endothelial cell-cell interactions and CCM lesions. We are studying CCM3, CCM2 and KRIT1 using a structure-directed functional approach and have determined the first crystal structures of each of these proteins.
Integrins are transmembrane receptors that play essential roles during development, tissue formation, hemostasis, and in response to injury and infection. We are particularly 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.
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 also investigating regulation mechanisms for downstream Rho-family effector molecules, and have discovered that the type II p21-activated kinases are regulated by pseudosubstrate autoinhibition.
Specialized Terms: Structural biology of signal transduction
- 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
- 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.
- 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.
- 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
- Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, Cheng E, Davis MJ, Goh G, Choi M, Ariyan S, Narayan D, Dutton-Regester K, Capatana A, Holman EC, Bosenberg M, Sznol M, Kluger HM, Brash DE, Stern DF, Materin MA, Lo RS, Mane S, Ma S, Kidd KK, Hayward NK, Lifton RP, Schlessinger J, Boggon TJ, Halaban R. Nature Genetics. 2012; 44(9):1006-1014
- RAC1-P29S is a spontaneously activating cancer-associated GTPase. Davis MJ, Ha BH, Holman EC, Halaban R, Schlessinger J, Boggon TJ. Proceedings of the National Academy of Sciences, U.S.A. 2013; 110(3):912-917.
- 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.