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Address: 2-481 BSB
Phone: (319) 384-4563
Mentor: Songhai Chen, MD, PhD
Undergraduate Institution: Marist College, BS
Year Entered Into Program: 2009
Rho guanine nucleotide exchange factors (GEFs) catalyze the activation of the Rho family of small GTPases to induce numerous downstream effects including cytoskeletal reorganization and DNA synthesis. Overexpression of RhoGEFs has been implicated in many human diseases, including cardiovascular disease and cancer, due to aberrant cell growth and migration associated with enhanced RhoGTPase activity. Currently, over 70 RhoGEFs have been identified that activate 25 RhoGTPases in a tissue- and RhoGTPase-specific manner. Of these, more than 60 are members of the dbl family of RhoGEFS, which can be activated through both growth factor receptors and G protein coupled receptors (GPCRs). A small subset of dbl RhoGEFs can be directly activated by the Gα or Gβγ subunits of the heterotrimeric G proteins. However, except for a few cases, the molecular mechanisms by which G proteins, particularly Gβγ, activates RhoGEFs remain largely unknown. My work focuses on PLEKHG2, a novel dbl RhoGEF that was activated by Gβγ. Previous studies show that upregulation of PLEKHG2 is associated with cell transformation and leukemia. Moreover, the PLEKHG2 gene maps to the 19q13 chromosome, a region commonly upregulated in many cancers, including breast cancer. Enhanced RhoGTPase signaling has been associated with breast cancer growth and metastasis. Moreover, our lab recently obtained evidence that Gβγ integrates signals from multiple GPCRs to promote breast cancer tumor growth and metastasis. Based on these findings, we hypothesize that Gβγ signaling via PLEKHG2 is critical for breast tumor growth and/or metastasis. Towards this, we will elucidate the molecular mechanism by which PLEKHG2 is activated by Gβγ and identify the RhoGTPases that are regulated by PLEKHG2. Additionally, we will determine the role of PLEKHG2 in the tumorigenesis and metastasis of breast cancer using both tissue culture and animal models.
Runne, C., and Chen, S.: WD40-Repeat Proteins Control the Flow of Gbg Signaling for Directional Cell Migration. Cell Adhesion and Migration 7(2):214-218, 2013. PMID: 23302952 [PubMed - in Process]
Sun, Z., Runne, C., Tang, X., Lin, F., and Chen, S.: The Gb3 splice variant associated with the C825T gene polymorphism is a functionally inactive and unstable protein. Cell Signal. 24(12):2349-59, 2012. PMCID: PMC22940628
Tang, X., Sun, Z., Runne, C., Madsen, J., Domann, F., Henry, M., Lin, F., and Chen, S.: A critical role of Gbg in tumorigenesis and metastasis of breast cancer. J. Biol. Chem. 286(15):13244-54, 2011. PMCID: PMC3075671
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