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

Cash, Jennifer N.; Davis, Ellen M.; Tesmer, John J. G.

doi:10.1016/j.str.2016.02.022

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

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.

Authors:: Cash, Jennifer N.; Davis, Ellen M.; Tesmer, John J. G.

Publication Date:: Sun May 01 00:00:00 EDT 2016

Research Org.:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Org.:: USDOE Office of Science (SC); National Institutes of Health (NIH); Michigan Economic Development Corp.; Michigan Technology Tri-Corridor

OSTI Identifier:: 1355064

Alternate Identifier(s):: OSTI ID: 1255291

Grant/Contract Number:: AC02-06CH11357; HL086865; HL122416; 085P1000817; DK20572

Resource Type:: Journal Article: Published Article

Journal Name:: Structure

Additional Journal Information:: Journal Name: Structure Journal Volume: 24 Journal Issue: 5; Journal ID: ISSN 0969-2126

Publisher:: Elsevier

Country of Publication:: United Kingdom

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats


                    Cash, Jennifer N., Davis, Ellen M., and Tesmer, John J. G. Structural and Biochemical Characterization of the Catalytic Core of the Metastatic Factor P-Rex1 and Its Regulation by PtdIns(3,4,5)P3.  United Kingdom: N. p., 2016. 
        Web.  doi:10.1016/j.str.2016.02.022.

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                    Cash, Jennifer N., Davis, Ellen M., & Tesmer, John J. G. Structural and Biochemical Characterization of the Catalytic Core of the Metastatic Factor P-Rex1 and Its Regulation by PtdIns(3,4,5)P3.  United Kingdom.  https://doi.org/10.1016/j.str.2016.02.022

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                    Cash, Jennifer N., Davis, Ellen M., and Tesmer, John J. G. 2016.  
        "Structural and Biochemical Characterization of the Catalytic Core of the Metastatic Factor P-Rex1 and Its Regulation by PtdIns(3,4,5)P3".  United Kingdom.  https://doi.org/10.1016/j.str.2016.02.022.

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@article{osti_1355064,

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

  author       = {Cash, Jennifer N. and Davis, Ellen M. and Tesmer, John J. G.},

  abstractNote = {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.},

  doi          = {10.1016/j.str.2016.02.022},

  url          = {https://www.osti.gov/biblio/1355064},
  journal      = {Structure},

  issn         = {0969-2126},

  number       = 5,

  volume       = 24,

  place        = {United Kingdom},

  year         = {Sun May 01 00:00:00 EDT 2016},

  month        = {Sun May 01 00:00:00 EDT 2016}

}

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

Abstract

Citation Formats

Deciphering the Molecular and Functional Basis of Dbl Family Proteins: A NOVEL SYSTEMATIC APPROACH TOWARD CLASSIFICATION OF SELECTIVE ACTIVATION OF THE Rho FAMILY PROTEINS journal, December 2012

Refinement of Macromolecular Structures by the Maximum-Likelihood Method journal, May 1997

Overview of the CCP 4 suite and current developments journal, March 2011

BALBES : a molecular-replacement pipeline journal, December 2007

Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1 journal, December 2000

Structural Basis for Discrimination of 3-Phosphoinositides by Pleckstrin Homology Domains journal, August 2000

Melanoma genome sequencing reveals frequent PREX2 mutations journal, May 2012

Membrane Translocation of P-Rex1 Is Mediated by G Protein βγ Subunits and Phosphoinositide 3-Kinase journal, October 2007

Towards automated crystallographic structure refinement with phenix.refine journal, March 2012

A conserved hydrophobic surface of the LARG pleckstrin homology domain is critical for RhoA activation in cells journal, November 2009

Specific and high-affinity binding of inositol phosphates to an isolated pleckstrin homology domain. journal, November 1995

Why does cancer therapy lack effective anti-metastasis drugs? journal, January 2013

Hallmarks of Cancer: The Next Generation journal, March 2011

The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients journal, May 2010

Identification of the Rac-GEF P-Rex1 as an Essential Mediator of ErbB Signaling in Breast Cancer journal, December 2010

Synergistic induction of cancer cell migration regulated by Gβγ and phosphatidylinositol 3-kinase journal, January 2012

Domain–domain interaction of P-Rex1 is essential for the activation and inhibition by G protein βγ subunits and PKA journal, August 2008

The Crystal Structure of Cdc42 in Complex with Collybistin II, a Gephyrin-interacting Guanine Nucleotide Exchange Factor journal, May 2006

P-Rex1 is required for efficient melanoblast migration and melanoma metastasis journal, September 2011

Structural Determinants of RhoA Binding and Nucleotide Exchange in Leukemia-associated Rho Guanine-Nucleotide Exchange Factor journal, August 2004

Characterization of the Pleckstrin Homology Domain of Btk as an Inositol Polyphosphate and Phosphoinositide Binding Domain journal, July 1997

Pathway of phosphatidylinositol(3,4,5)-trisphosphate synthesis in activated neutrophils journal, May 1991

Signaling requirements for translocation of P-Rex1, a key Rac2 exchange factor involved in chemoattractant-stimulated human neutrophil function journal, January 2007

CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling journal, August 2007

P-Rex1 Cooperates with PDGFRβ to Drive Cellular Migration in 3D Microenvironments journal, January 2013

Crystal Structure of the Rac Activator, Asef, Reveals Its Autoinhibitory Mechanism* journal, February 2007

Activated RhoA Binds to the Pleckstrin Homology (PH) Domain of PDZ-RhoGEF, a Potential Site for Autoregulation journal, April 2010

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The Importance of Interaction with Membrane Lipids through the Pleckstrin Homology Domain of the Guanine Nucleotide Exchange Factor for Rho Family Small Guanosine Triphosphatase, FLJ00018 journal, January 2013

Features and development of Coot journal, March 2010

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P-REX2, a novel PI-3-kinase sensitive Rac exchange factor journal, July 2004

P-Rex2, a new guanine-nucleotide exchange factor for Rac journal, July 2004

Structural basis for the selective activation of Rho GTPases by Dbl exchange factors journal, May 2002

The Phosphatidylinositol (3,4,5)-Trisphosphate-dependent Rac Exchanger 1·Ras-related C3 Botulinum Toxin Substrate 1 (P-Rex1·Rac1) Complex Reveals the Basis of Rac1 Activation in Breast Cancer Cells journal, August 2015

P-Rex1 Regulates Neutrophil Function journal, October 2005

Structural Basis of 3-Phosphoinositide Recognition by Pleckstrin Homology Domains journal, August 2000

Regulation of P-Rex1 by Phosphatidylinositol (3,4,5)-Trisphosphate and Gβγ Subunits journal, November 2004

Multifunctional Roles for the PH Domain of Dbs in Regulating Rho GTPase Activation journal, May 2003

Structural insights into the regulation of PDK1 by phosphoinositides and inositol phosphates journal, September 2004

P-Rex1 Is a Primary Rac2 Guanine Nucleotide Exchange Factor in Mouse Neutrophils journal, October 2005

Systematic analysis of domain motions in proteins from conformational change: New results on citrate synthase and T4 lysozyme journal, February 1998

Molecular Pharmacology and Antitumor Activity of PHT-427, a Novel Akt/Phosphatidylinositide-Dependent Protein Kinase 1 Pleckstrin Homology Domain Inhibitor journal, March 2010

Upregulation of PIP3-dependent Rac exchanger 1 (P-Rex1) promotes prostate cancer metastasis journal, March 2009

Loss of Phosphatidylinositol 3-Phosphate Binding by the C-terminal Tiam-1 Pleckstrin Homology Domain Prevents in Vivo Rac1 Activation without Affecting Membrane Targeting journal, January 2003

Differences in Gα12- and Gα13-mediated plasma membrane recruitment of p115-RhoGEF journal, June 2009

Phaser crystallographic software journal, July 2007

P-Rex1, a PtdIns(3,4,5)P3- and Gβγ-Regulated Guanine-Nucleotide Exchange Factor for Rac journal, March 2002

Deciphering the Molecular and Functional Basis of Dbl Family Proteins: A NOVEL SYSTEMATIC APPROACH TOWARD CLASSIFICATION OF SELECTIVE ACTIVATION OF THE Rho FAMILY PROTEINS
journal, December 2012

Refinement of Macromolecular Structures by the Maximum-Likelihood Method
journal, May 1997

Overview of the CCP 4 suite and current developments
journal, March 2011

BALBES : a molecular-replacement pipeline
journal, December 2007

Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1
journal, December 2000

Structural Basis for Discrimination of 3-Phosphoinositides by Pleckstrin Homology Domains
journal, August 2000

Melanoma genome sequencing reveals frequent PREX2 mutations
journal, May 2012

Membrane Translocation of P-Rex1 Is Mediated by G Protein βγ Subunits and Phosphoinositide 3-Kinase
journal, October 2007

Towards automated crystallographic structure refinement with phenix.refine
journal, March 2012

A conserved hydrophobic surface of the LARG pleckstrin homology domain is critical for RhoA activation in cells
journal, November 2009

Specific and high-affinity binding of inositol phosphates to an isolated pleckstrin homology domain.
journal, November 1995

Why does cancer therapy lack effective anti-metastasis drugs?
journal, January 2013

Hallmarks of Cancer: The Next Generation
journal, March 2011

The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients
journal, May 2010

Identification of the Rac-GEF P-Rex1 as an Essential Mediator of ErbB Signaling in Breast Cancer
journal, December 2010

Synergistic induction of cancer cell migration regulated by Gβγ and phosphatidylinositol 3-kinase
journal, January 2012

Domain–domain interaction of P-Rex1 is essential for the activation and inhibition by G protein βγ subunits and PKA
journal, August 2008

The Crystal Structure of Cdc42 in Complex with Collybistin II, a Gephyrin-interacting Guanine Nucleotide Exchange Factor
journal, May 2006

P-Rex1 is required for efficient melanoblast migration and melanoma metastasis
journal, September 2011

Structural Determinants of RhoA Binding and Nucleotide Exchange in Leukemia-associated Rho Guanine-Nucleotide Exchange Factor
journal, August 2004

Characterization of the Pleckstrin Homology Domain of Btk as an Inositol Polyphosphate and Phosphoinositide Binding Domain
journal, July 1997

Pathway of phosphatidylinositol(3,4,5)-trisphosphate synthesis in activated neutrophils
journal, May 1991

Signaling requirements for translocation of P-Rex1, a key Rac2 exchange factor involved in chemoattractant-stimulated human neutrophil function
journal, January 2007

CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling
journal, August 2007

P-Rex1 Cooperates with PDGFRβ to Drive Cellular Migration in 3D Microenvironments
journal, January 2013

Crystal Structure of the Rac Activator, Asef, Reveals Its Autoinhibitory Mechanism*
journal, February 2007

Activated RhoA Binds to the Pleckstrin Homology (PH) Domain of PDZ-RhoGEF, a Potential Site for Autoregulation
journal, April 2010

MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009

Role of guanine nucleotide exchange factor P-Rex-2b in sphingosine 1-phosphate-induced Rac1 activation and cell migration in endothelial cells
journal, May 2005

The Importance of Interaction with Membrane Lipids through the Pleckstrin Homology Domain of the Guanine Nucleotide Exchange Factor for Rho Family Small Guanosine Triphosphatase, FLJ00018
journal, January 2013

Features and development of Coot
journal, March 2010

Differential Sensitivity of P-Rex1 to Isoforms of G Protein βγ Dimers
journal, January 2006

P-REX2, a novel PI-3-kinase sensitive Rac exchange factor
journal, July 2004

P-Rex2, a new guanine-nucleotide exchange factor for Rac
journal, July 2004

Structural basis for the selective activation of Rho GTPases by Dbl exchange factors
journal, May 2002

The Phosphatidylinositol (3,4,5)-Trisphosphate-dependent Rac Exchanger 1·Ras-related C3 Botulinum Toxin Substrate 1 (P-Rex1·Rac1) Complex Reveals the Basis of Rac1 Activation in Breast Cancer Cells
journal, August 2015

P-Rex1 Regulates Neutrophil Function
journal, October 2005

Structural Basis of 3-Phosphoinositide Recognition by Pleckstrin Homology Domains
journal, August 2000

Regulation of P-Rex1 by Phosphatidylinositol (3,4,5)-Trisphosphate and Gβγ Subunits
journal, November 2004

Multifunctional Roles for the PH Domain of Dbs in Regulating Rho GTPase Activation
journal, May 2003

Structural insights into the regulation of PDK1 by phosphoinositides and inositol phosphates
journal, September 2004

P-Rex1 Is a Primary Rac2 Guanine Nucleotide Exchange Factor in Mouse Neutrophils
journal, October 2005

Systematic analysis of domain motions in proteins from conformational change: New results on citrate synthase and T4 lysozyme
journal, February 1998

Molecular Pharmacology and Antitumor Activity of PHT-427, a Novel Akt/Phosphatidylinositide-Dependent Protein Kinase 1 Pleckstrin Homology Domain Inhibitor
journal, March 2010

Upregulation of PIP3-dependent Rac exchanger 1 (P-Rex1) promotes prostate cancer metastasis
journal, March 2009

Loss of Phosphatidylinositol 3-Phosphate Binding by the C-terminal Tiam-1 Pleckstrin Homology Domain Prevents in Vivo Rac1 Activation without Affecting Membrane Targeting
journal, January 2003

Differences in Gα12- and Gα13-mediated plasma membrane recruitment of p115-RhoGEF
journal, June 2009

Phaser crystallographic software
journal, July 2007

P-Rex1, a PtdIns(3,4,5)P3- and Gβγ-Regulated Guanine-Nucleotide Exchange Factor for Rac
journal, March 2002