GPCRs can induce changes in the actin cytoskeleton and in gene transcription by activating effectors that exchange nucleotides on Rho family GTPases. In 2004, the lab reported the atomic structures of the catalytic domains of Leukemia-associated RhoGEF alone and in complex with RhoA, and in 2006, the structures of the oncogenic Gα12 and Gα13 subunits that regulate the activity of this enzyme. The lab went on to determine the structure of the Gαq -p63RhoGEF-RhoA complex (1), illustrating a novel Gαq signaling pathway that plays a role in cardiac hypertrophy. More recently, the Tesmer lab has been characterizing Trio (2), a Gαq -regulated enzyme directly implicated in uveal melanoma, and P-Rex1, a Gβγ-regulated RhoGEF that plays a key role in both neutrophil migration and metastasis (3, 4).
Publications
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Lutz S, Shankaranarayanan A, Coco C, Ridilla M, Nance MR, Vettel C, Baltus D, Evelyn CR, Neubig RR, Wieland T, Tesmer JJ. Structure of Gαq -p63RhoGEF-RhoA complex reveals a pathway for the activation of RhoA by GPCRs. Science. 2007 318:1923-7. PMID: 18096806
- Bandekar SJ, Arang N, Tang BA, Tully ES, Barton BL, Li S, Gutkind JS, and Tesmer JJG: Structure of the C-terminal guanine exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential. Sci Signal. 2019, 12: pii: eaav2449. doi: 10.1126/scisignal.aav2449. PMC6519057
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Cash JN, Davis EM, Tesmer JJG: Structural and biochemical characterization of the catalytic core of the metastatic factor P-Rex1 and its regulation by PtdIns(3,4,5)P3. Structure 2016, 24:730-40. PMC4860252
- Cash JN, Urata S, Li S, Ravala S, Avramova L, Gutkind JS, Tesmer JJG, Cianfrocco MA: Cryo-electron microscopy structure and analyses of the P-Rex1–Gβγ complex signaling scaffold. Sci Advances 2019, 5: eaax8855. PMC6795519