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Structural and Biochemical Characterization of the Catalytic Core of the Metastatic Factor P-Rex1 and Its Regulation by PtdIns(3,4,5)P3.

Cash JN, Davis EM, Tesmer JJG
Structure 24 730-740 (2016)
Related entries: 5d27, 5d3v, 5d3w, 5d3y, 5fi0, 5fi1

Cited: 24 times
EuropePMC logo PMID: 27150042

Abstract

Phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchanger 1 (P-Rex1) is a Rho guanine nucleotide exchange factor synergistically activated by PIP3 and Gβγ that plays an important role in the metastasis of breast, prostate, and skin cancer, making it an attractive therapeutic target. However, the molecular mechanisms behind P-Rex1 regulation are poorly understood. We determined structures of the P-Rex1 pleckstrin homology (PH) domain bound to the headgroup of PIP3 and resolved that PIP3 binding to the PH domain is required for P-Rex1 activity in cells but not for membrane localization, which points to an allosteric activation mechanism by PIP3. We also determined structures of the P-Rex1 tandem Dbl homology/PH domains in complexes with two of its substrate GTPases, Rac1 and Cdc42. Collectively, this study provides important molecular insights into P-Rex1 regulation and tools for targeting the PIP3-binding pocket of P-Rex1 with a new generation of cancer chemotherapeutic agents.

Articles - 5d3x mentioned but not cited (5)

  1. Structural and Biochemical Characterization of the Catalytic Core of the Metastatic Factor P-Rex1 and Its Regulation by PtdIns(3,4,5)P3. Cash JN, Davis EM, Tesmer JJG. Structure 24 730-740 (2016)
  2. Cryo-electron microscopy structure and analysis of the P-Rex1-Gβγ signaling scaffold. Cash JN, Urata S, Li S, Ravala SK, Avramova LV, Shost MD, Gutkind JS, Tesmer JJG, Cianfrocco MA. Sci Adv 5 eaax8855 (2019)
  3. Systematic simulation of the interactions of pleckstrin homology domains with membranes. Le Huray KIP, Wang H, Sobott F, Kalli AC. Sci Adv 8 eabn6992 (2022)
  4. Structural and biochemical characterization of the pleckstrin homology domain of the RhoGEF P-Rex2 and its regulation by PIP3. Cash JN, Sharma PV, Tesmer JJG. J Struct Biol X 1 100001 (2019)
  5. research-article Structural and dynamic changes in P-Rex1 upon activation by PIP 3 and inhibition by IP 4. Ravala SK, Adame-Garcia SR, Li S, Chen CL, Cianfrocco MA, Gutkind JS, Cash JN, Tesmer JJG. bioRxiv 2023.09.15.557836 (2023)


Reviews citing this publication (5)

  1. Rac1 Signaling: From Intestinal Homeostasis to Colorectal Cancer Metastasis. Kotelevets L, Chastre E. Cancers (Basel) 12 E665 (2020)
  2. P-Rex1 and P-Rex2 RacGEFs and cancer. Srijakotre N, Man J, Ooms LM, Lucato CM, Ellisdon AM, Mitchell CA. Biochem Soc Trans 45 963-977 (2017)
  3. Polyphosphoinositide-Binding Domains: Insights from Peripheral Membrane and Lipid-Transfer Proteins. Pemberton JG, Balla T. Adv Exp Med Biol 1111 77-137 (2019)
  4. The P-Rex1/Rac signaling pathway as a point of convergence for HER/ErbB receptor and GPCR responses. Kazanietz MG, Barrio-Real L, Casado-Medrano V, Baker MJ, Lopez-Haber C. Small GTPases 9 297-303 (2018)
  5. Rho Family GTPases and Rho GEFs in Glucose Homeostasis. Machin PA, Tsonou E, Hornigold DC, Welch HCE. Cells 10 915 (2021)

Articles citing this publication (14)

  1. PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs). Barrows D, He JZ, Parsons R. J Biol Chem 291 20042-20054 (2016)
  2. Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential. Bandekar SJ, Arang N, Tully ES, Tang BA, Barton BL, Li S, Gutkind JS, Tesmer JJG. Sci Signal 12 eaav2449 (2019)
  3. Analysis of Ras-effector interaction competition in large intestine and colorectal cancer context. Ibáňez Gaspar V, Catozzi S, Ternet C, Luthert PJ, Kiel C. Small GTPases 12 209-225 (2021)
  4. The guanine nucleotide exchange factor Arhgef7/βPix promotes axon formation upstream of TC10. López Tobón A, Suresh M, Jin J, Vitriolo A, Pietralla T, Tedford K, Bossenz M, Mahnken K, Kiefer F, Testa G, Fischer KD, Püschel AW. Sci Rep 8 8811 (2018)
  5. Gαs directly drives PDZ-RhoGEF signaling to Cdc42. Castillo-Kauil A, García-Jiménez I, Cervantes-Villagrana RD, Adame-García SR, Beltrán-Navarro YM, Gutkind JS, Reyes-Cruz G, Vázquez-Prado J. J Biol Chem 295 16920-16928 (2020)
  6. Regulation of local GTP availability controls RAC1 activity and cell invasion. Bianchi-Smiraglia A, Wolff DW, Marston DJ, Deng Z, Han Z, Moparthy S, Wombacher RM, Mussell AL, Shen S, Chen J, Yun DH, O'Brien Cox A, Furdui CM, Hurley E, Feltri ML, Qu J, Hollis T, Kengne JBN, Fongang B, Sousa RJ, Kandel ME, Kandel ES, Hahn KM, Nikiforov MA. Nat Commun 12 6091 (2021)
  7. Discovery of Small Molecules That Target the Phosphatidylinositol (3,4,5) Trisphosphate (PIP3)-Dependent Rac Exchanger 1 (P-Rex1) PIP3-Binding Site and Inhibit P-Rex1-Dependent Functions in Neutrophils. Cash JN, Chandan NR, Hsu AY, Sharma PV, Deng Q, Smrcka AV, Tesmer JJG. Mol Pharmacol 97 226-236 (2020)
  8. Basic-hydrophobic sites are localized in conserved positions inside and outside of PH domains and affect localization of Dictyostelium myosin 1s. Brzeska H, Gonzalez J, Korn ED, Titus MA. Mol Biol Cell 31 101-117 (2020)
  9. The first DEP domain of the RhoGEF P-Rex1 autoinhibits activity and contributes to membrane binding. Ravala SK, Hopkins JB, Plescia CB, Allgood SR, Kane MA, Cash JN, Stahelin RV, Tesmer JJG. J Biol Chem 295 12635-12647 (2020)
  10. Structure of the metastatic factor P-Rex1 reveals a two-layered autoinhibitory mechanism. Chang YG, Lupton CJ, Bayly-Jones C, Keen AC, D'Andrea L, Lucato CM, Steele JR, Venugopal H, Schittenhelm RB, Whisstock JC, Halls ML, Ellisdon AM. Nat Struct Mol Biol 29 767-773 (2022)
  11. The pseudokinase NRBP1 activates Rac1/Cdc42 via P-Rex1 to drive oncogenic signalling in triple-negative breast cancer. Yang X, Cruz MI, Nguyen EV, Huang C, Schittenhelm RB, Luu J, Cowley KJ, Shin SY, Nguyen LK, Lim Kam Sian TCC, Clark KC, Simpson KJ, Ma X, Daly RJ. Oncogene 42 833-847 (2023)
  12. Small-molecule inhibitors of P-Rex guanine-nucleotide exchange factors. Lawson CD, Hornigold K, Pan D, Niewczas I, Andrews S, Clark J, Welch H. Small GTPases 13 307-326 (2022)
  13. Structural Dynamics of P-Rex1 Complexed with Natural Leads Establishes the Protein as an Attractive Target for Therapeutics to Suppress Cancer Metastasis. Hameed AR, Ali SF, Alsallameh SMS, Muhseen ZT, Almansour NM, ALSuhaymi N, Alsugoor MH, Allemailem KS. Biomed Res Int 2023 3882081 (2023)
  14. Structural Insights Uncover the Specific Phosphoinositide Recognition by the PH1 Domain of Arap3. Zhang Y, Ge L, Xu L, Liu Y, Wang J, Liu C, Zhao H, Xing L, Wang J, Wu B. Int J Mol Sci 24 1125 (2023)


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