%0 Journal Article %A Ellyn R. Montgomery %A Brenda R.S. Temple %A Kimberly A. Peters %A Caitlin E. Tolbert %A Brandon K. Booker %A Joseph W. Martin %A Tyler P. Hamilton %A Alicia C. Tagliatela %A William C. Smolski %A Stephen L. Rogers %A Alan M. Jones %A Thomas E. Meigs %T Gα12 Structural Determinants of Hsp90 Interaction are Necessary for Serum Response Element-mediated Transcriptional Activation %D 2014 %R 10.1124/mol.113.088443 %J Molecular Pharmacology %P mol.113.088443 %X The G12/13 class of heterotrimeric G proteins, comprised of the α subunits Gα12 and Gα13, regulates multiple aspects of cellular behavior including proliferation and cytoskeletal rearrangements. Although guanine nucleotide exchange factors for the monomeric G protein Rho (RhoGEFs) are well-characterized as effectors of this G protein class, a variety of other downstream targets have been reported. To identify Gα12 determinants that mediate specific protein interactions, we utilized a structural and evolutionary comparison between the G12/13, Gs, Gi, and Gq classes to identify "class-distinctive" residues in Gα12 and Gα13. Mutation of these residues in Gα12 to their deduced ancestral forms revealed a subset necessary for activation of serum response element (SRE)-mediated transcription, a G12/13-stimulated pathway implicated in cell proliferative signaling. Unexpectedly, this subset of Gα12 mutants showed impaired binding to heat shock protein-90 (Hsp90) while retaining binding to RhoGEFs. Corresponding mutants of Gα13 exhibited robust SRE activation, suggesting a Gα12-specific mechanism, and inhibition of Hsp90 by geldanamycin or siRNA-mediated lowering of Hsp90 levels resulted in greater down-regulation of Gα12 than Gα13 signaling in SRE activation experiments. Furthermore, the Drosophila G12/13 homolog Concertina was unable to signal to SRE in mammalian cells, and Gα12:Concertina chimeras revealed Gα12-specific determinants of SRE activation within the Switch regions and a C-terminal region. These findings identify Gα12 determinants of SRE activation, implicate Gα12:Hsp90 interaction in this signaling mechanism, and illuminate structural features that arose during evolution of Gα12 and Gα13 to allow bifurcated mechanisms of signaling to a common cell proliferative pathway. %U https://molpharm.aspetjournals.org/content/molpharm/early/2014/01/16/mol.113.088443.full.pdf