Cell migration is a fundamental process required for embryogenesis, angiogenesis, wound healing and immune responses, and abnormalities in this process are associated with a plethora of pathological conditions including autoimmune diseases, arthrosclerosis and tumor metastasis. Cell migration is regulated by chemoattractants acting on cell-surface receptors belonging to the large family of G protein-coupled receptors. These receptors typically couple to G proteins of the Gi/o class, and mediate their functions through Gbg dimers. Although the essential role of Gbg in cell migration has been well established, it is still unclear how Gbg activate downstream effectors to generate a highly polarized intracellular signal that acts as an internal "compass" to drive directional cell migration. We have recently identified novel interactions between Gbg and the WD40 repeat proteins RACK1 (receptor for activated C kinase 1) and WDR26. Based on the findings that RACK1 and WDR26 are localized at the leading edge of a polarized leukocyte and negatively and positively regulate Gbg signaling, respectively, we hypothesize that reciprocal interactions of Gbg with WDR26 and RACK1 are important positive and negative feedback regulations for the coordinated Gbg signaling at the leading edge that drives leukocyte polarization and directed migration.
In Aim 1, we will explore the molecular mechanism by which WDR26 interacts with Gbg and its effectors including PI3Ks and PLCb to promote Gbg signaling and generate a highly polarized intracellular response at the leading edge for leukocyte migration.
In Aim 2, we will determine how RACK1 restricts Gbg signaling for the generation of a locally amplified signal at the leading edge and for signal adaptation and directional sensing. Finally, we will dissect the molecular signals that control the reciprocal interactions of WDR26 and RACK1 with Gbg and determine the impact of the balance of these interactions on leukocyte migration. These studies have the potential to close a critical gap in our understanding of how chemoattractants transmit through Gbg to generate a spatially localized cellular signal at the leading edge that drives leukocyte migration, and to unveil a novel mechanism of regulating chemotaxis at the level of G proteins upstream to all known signaling pathways essential for cell migration. Given the involvement of abnormal leukocyte migration in many pathological conditions, the proposed research will be vital for identifying novel targets to enable selective interference of the signaling pathways related to disease development. Thus, this work has high biological significance and potential impact on human health.
This application proposes to study the mechanisms underlying leukocyte migration. The study is expected to contribute significantly to the development of new therapies for the treatment of diseases related to abnormal leukocyte migration including autoimmune diseases, cardiovascular diseases and tumor metastasis.
|Ye, Yuanchao; Tang, Xiaoyun; Sun, Zhizeng et al. (2016) Upregulated WDR26 serves as a scaffold to coordinate PI3K/ AKT pathway-driven breast cancer cell growth, migration, and invasion. Oncotarget 7:17854-69|
|Xie, Qing; Klesney-Tait, Julia; Keck, Kathy et al. (2015) Characterization of a novel mouse model with genetic deletion of CD177. Protein Cell 6:117-26|
|Ye, Yuanchao; Sun, Zhizeng; Guo, Ang et al. (2014) Ablation of the GNB3 gene in mice does not affect body weight, metabolism or blood pressure, but causes bradycardia. Cell Signal 26:2514-20|
|Xu, Hui; Ye, Ding; Behra, Martine et al. (2014) G*1 controls collective cell migration by regulating the protrusive activity of leader cells in the posterior lateral line primordium. Dev Biol 385:316-27|
|Sun, Zhizeng; Smrcka, Alan V; Chen, Songhai (2013) WDR26 functions as a scaffolding protein to promote GÎ²Î³-mediated phospholipase C Î²2 (PLCÎ²2) activation in leukocytes. J Biol Chem 288:16715-25|
|Runne, Caitlin; Chen, Songhai (2013) PLEKHG2 promotes heterotrimeric G protein Î²Î³-stimulated lymphocyte migration via Rac and Cdc42 activation and actin polymerization. Mol Cell Biol 33:4294-307|
|Runne, Caitlin; Chen, Songhai (2013) WD40-repeat proteins control the flow of GÎ²Î³ signaling for directional cell migration. Cell Adh Migr 7:214-8|
|Sun, Zhizeng; Runne, Caitlin; Tang, Xiaoyun et al. (2012) The GÎ²3 splice variant associated with the C825T gene polymorphism is an unstable and functionally inactive protein. Cell Signal 24:2349-59|
|Xu, Hui; Kardash, Elena; Chen, Songhai et al. (2012) GÎ²Î³ signaling controls the polarization of zebrafish primordial germ cells by regulating Rac activity. Development 139:57-62|
|Sun, Zhizeng; Tang, Xiaoyun; Lin, Fang et al. (2011) The WD40 repeat protein WDR26 binds GÎ²Î³ and promotes GÎ²Î³-dependent signal transduction and leukocyte migration. J Biol Chem 286:43902-12|