The long-term objective of our research is to understand the signaling mechanisms of heterotrimeric guanine nucleotide-binding regulatory proteins (G proteins). The main focus of this application is on the molecular signaling mechanism of G protein Ga13. Ga13 -/- mice died at E9.5. Yet the molecular basis for this embryonic lethality is not clear. Since the yolk sac of Ga13 -/- mouse embryos (at E9.5) did not show any blood vessels, it was postulated that the cause of death was a defective vascularization during embryogenesis. This early embryonic lethality of Ga13 -/- mice makes the study of the role and molecular basis for Ga13 in embryonic angiogenesis difficult. Therefore, we will use tumor angiogenesis as a model to investigate the function of Ga13 in adult angiogenesis in mice in the Specific Aim 1. In the Specific Aim 2, we will explore the molecular mechanism by which Ga13 contributes to adult angiogenesis. G proteins are known as signaling mediators downstream of G protein-coupled receptors. Our recent finding of a critical role for Ga13 in receptor tyrosine kinase-initiated signaling immediately begs the question of how receptor tyrosine kinases signal to Ga13. We will investigate the biochemical and cellular signaling mechanisms by which growth factor receptors transmit the signals to Ga13 in a GPCR-independent manner in the Specific Aim 3.
This research is directly related to human health. Cell migration and angiogenesis are essential for vascular development and tumor growth. Furthermore, effective neovascularization induced by endothelial progenitor cell transplantation for hind limb, myocardial, and cerebral ischemia has been demonstrated in many preclinical studies, and early clinical trials of endothelial progenitor cells transplantation in chronic and acute coronary artery diseases indicate safety and feasibility of cell-based therapies. Therefore, a better understanding of the mechanisms of angiogenesis and of the migration/recruitment of endothelial progenitor cells will advance our combat against cardiovascular diseases and cancers.
|Syrovatkina, Viktoriya; Alegre, Kamela O; Dey, Raja et al. (2016) Regulation, Signaling, and Physiological Functions of G-Proteins. J Mol Biol 428:3850-68|
|Zhang, Wenjun; Qu, Xiuxia; Chen, Biyi et al. (2016) Critical Roles of STAT3 in Î²-Adrenergic Functions in the Heart. Circulation 133:48-61|
|Huang, Jianyun; Sun, Yutong; Zhang, J Jillian et al. (2015) Pivotal role of extended linker 2 in the activation of GÎ± by G protein-coupled receptor. J Biol Chem 290:272-83|
|Yao, Qi; Liu, Bing-Qian; Li, Hui et al. (2014) C-terminal Src kinase (Csk)-mediated phosphorylation of eukaryotic elongation factor 2 (eEF2) promotes proteolytic cleavage and nuclear translocation of eEF2. J Biol Chem 289:12666-78|
|Xing, Bowen; Wang, Limin; Guo, Dagang et al. (2013) Atypical protein kinase CÎ» is critical for growth factor receptor-induced dorsal ruffle turnover and cell migration. J Biol Chem 288:32827-36|
|Huang, Jianyun; Chen, Shuai; Zhang, J Jillian et al. (2013) Crystal structure of oligomeric Î²1-adrenergic G protein-coupled receptors in ligand-free basal state. Nat Struct Mol Biol 20:419-25|
|Wang, Limin; Guo, Dagang; Xing, Bowen et al. (2011) Resistance to inhibitors of cholinesterase-8A (Ric-8A) is critical for growth factor receptor-induced actin cytoskeletal reorganization. J Biol Chem 286:31055-61|
|Snyder, Marylynn; Huang, Xin-Yun; Zhang, J Jillian (2010) Stat3 directly controls the expression of Tbx5, Nkx2.5, and GATA4 and is essential for cardiomyocyte differentiation of P19CL6 cells. J Biol Chem 285:23639-46|
|Chen, Lin; Zhang, J Jillian; Rafii, Shahin et al. (2009) Suppression of tumor angiogenesis by Galpha(13) haploinsufficiency. J Biol Chem 284:27409-15|