Coordinating the Activation of RhoA by Diverse RhoGEFs: SmgGDS and G-alpha-q-Responsive Dbl Family Guanine Nucleotide Exchange Factors

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  • March 20, 2019
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  • Rojas, Rafael Jose
    • Affiliation: School of Medicine, Department of Pharmacology
Abstract
  • G proteins are molecular switches that fluctuate between on and off states and regulate a multitude of essential signaling cascades within the cell. G proteins implicated in signal transduction can be divided into two major groups, the heterotrimeric G proteins and the small GTPases, such as Rho. Rho-related GTPases are activated primarily by guanine nucleotide exchange factors (GEFs) of the Dbl family. Dbl family GEFs are regulated via a number of mechanisms and typically function as signaling nodes by coupling several major signal transduction cascades. Additionally, there is a subset of atypical GEFs for Rho GTPases that are not related to the conventional Dbl family. However, the mechanism by which atypical GEFs engage Rho GTPases is poorly defined. Here we present a study of guanine nucleotide exchange upon the small GTPase Rho mediated by two distinct exchange factors, the Dbl family member p63RhoGEF and the atypical GEF SmgGDS. We describe the novel mechanism by which p63RhoGEF is activated by the heterotrimeric G protein Gαq to stimulate guanine nucleotide exchange upon the small GTPase Rho. Additionally, we demonstrate the GTPase substrate specificity of SmgGDS and describe the preliminary crystallization of SmgGDS bound to Rho. Together, these studies further our knowledge of the underlying pathways and mechanisms by which the small GTPase Rho is activated.
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  • Sondek, John
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