The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain

Xu, Zhen; Gakhar, Lokesh; Bain, Fletcher E.; Spies, Maria; Fuentes, Ernesto J.

doi:10.1074/jbc.M117.799114

Title: The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain

Abstract

T-cell lymphoma invasion and metastasis 1 (Tiam1) is a Dbl-family guanine nucleotide exchange factor (GEF) that specifically activates the Rho-family GTPase Rac1 in response to upstream signals, thereby regulating cellular processes including cell adhesion and migration. Tiam1 contains multiple domains, including an N-terminal pleckstrin homology coiled-coiled extension (PH_n-CC-Ex) and catalytic Dbl homology and C-terminal pleckstrin homology (DH-PH_c) domain. Previous studies indicate that larger fragments of Tiam1, such as the region encompassing the N-terminal to C-terminal pleckstrin homology domains (PH_n-PH_c), are auto-inhibited. However, the domains in this region responsible for inhibition remain unknown. Here, we show that the PH_n-CC-Ex domain inhibits Tiam1 GEF activity by directly interacting with the catalytic DH-PH_c domain, preventing Rac1 binding and activation. Enzyme kinetics experiments suggested that Tiam1 is auto-inhibited through occlusion of the catalytic site rather than by allostery. Small angle X-ray scattering and ensemble modeling yielded models of the PH_n-PH_c fragment that indicate it is in equilibrium between “open” and “closed” conformational states. Lastly, single-molecule experiments support a model in which conformational sampling between the open and closed states of Tiam1 contributes to Rac1 dissociation. Our results highlight the role of the PH_n-CC-Ex domain in Tiam1 GEF regulation and suggest a combinatorial model formore »« less

Authors:

Xu, Zhen ^[1]; Gakhar, Lokesh ^[1]; Bain, Fletcher E. ^[1]; Spies, Maria ^[1];

^[1]

Univ. of Iowa, Iowa City, IA (United States)

Publication Date:: Thu Sep 07 00:00:00 EDT 2017

Research Org.:: Bettis Atomic Power Lab. (BAPL), West Mifflin, PA (United States)

Sponsoring Org.:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Inst. of Health; National Science Foundation (NSF)

OSTI Identifier:: 1432852

Grant/Contract Number:: AC02-05CH11231; AC02-06CH11357; R01 GM108617; MCB-0953080; NIH 5T32GM008365

Resource Type:: Accepted Manuscript

Journal Name:: Journal of Biological Chemistry

Additional Journal Information:: Journal Volume: 292; Journal Issue: 43; Journal ID: ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular Biology

Country of Publication:: United States

Language:: ENGLISH

Subject:: 59 BASIC BIOLOGICAL SCIENCES; enzyme kinetics; guanine nucleotide exchange factor (GEF); inhibition mechanism; Ras-related C3 botulinum toxin substrate 1 (Rac1); small-angle X-ray scattering (SAXS); single-molecule total internal reflection fluorescence microscopy; Tiam1; auto-inhibition; in vitro GEF assays

Citation Formats


                    Xu, Zhen, Gakhar, Lokesh, Bain, Fletcher E., Spies, Maria, and Fuentes, Ernesto J. The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain.  United States: N. p., 2017. 
Web.  doi:10.1074/jbc.M117.799114.

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                    Xu, Zhen, Gakhar, Lokesh, Bain, Fletcher E., Spies, Maria, & Fuentes, Ernesto J. The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain.  United States.  https://doi.org/10.1074/jbc.M117.799114

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                    Xu, Zhen, Gakhar, Lokesh, Bain, Fletcher E., Spies, Maria, and Fuentes, Ernesto J. Thu .  
"The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain".  United States.  https://doi.org/10.1074/jbc.M117.799114.  https://www.osti.gov/servlets/purl/1432852.

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@article{osti_1432852,

  title        = {The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain},

  author       = {Xu, Zhen and Gakhar, Lokesh and Bain, Fletcher E. and Spies, Maria and Fuentes, Ernesto J.},

  abstractNote = {T-cell lymphoma invasion and metastasis 1 (Tiam1) is a Dbl-family guanine nucleotide exchange factor (GEF) that specifically activates the Rho-family GTPase Rac1 in response to upstream signals, thereby regulating cellular processes including cell adhesion and migration. Tiam1 contains multiple domains, including an N-terminal pleckstrin homology coiled-coiled extension (PHn-CC-Ex) and catalytic Dbl homology and C-terminal pleckstrin homology (DH-PHc) domain. Previous studies indicate that larger fragments of Tiam1, such as the region encompassing the N-terminal to C-terminal pleckstrin homology domains (PHn-PHc), are auto-inhibited. However, the domains in this region responsible for inhibition remain unknown. Here, we show that the PHn-CC-Ex domain inhibits Tiam1 GEF activity by directly interacting with the catalytic DH-PHc domain, preventing Rac1 binding and activation. Enzyme kinetics experiments suggested that Tiam1 is auto-inhibited through occlusion of the catalytic site rather than by allostery. Small angle X-ray scattering and ensemble modeling yielded models of the PHn-PHc fragment that indicate it is in equilibrium between “open” and “closed” conformational states. Lastly, single-molecule experiments support a model in which conformational sampling between the open and closed states of Tiam1 contributes to Rac1 dissociation. Our results highlight the role of the PHn-CC-Ex domain in Tiam1 GEF regulation and suggest a combinatorial model for GEF inhibition and activation of the Rac1 signaling pathway.},

  doi          = {10.1074/jbc.M117.799114},

  journal      = {Journal of Biological Chemistry},

  number       = 43,

  volume       = 292,

  place        = {United States},

  year         = {Thu Sep 07 00:00:00 EDT 2017},

  month        = {Thu Sep 07 00:00:00 EDT 2017}

}

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Preparing Sample Chambers for Single-Molecule FRET
journal, October 2012

Joo, Chirlmin; Ha, Taekjip
Cold Spring Harbor Protocols, Vol. 2012, Issue 10
DOI: 10.1101/pdb.prot071530

Works referencing / citing this record:

Identification of guanine nucleotide exchange factors that increase Cdc42 activity in primary human endothelial cells
journal, August 2019

Reinhard, Nathalie R.; Van Der Niet, Sanne; Chertkova, Anna
Small GTPases
DOI: 10.1080/21541248.2019.1658509

Identification of guanine nucleotide exchange factors that increase Cdc42 activity in primary human endothelial cells
text, January 2019

Reinhard, Nathalie R.; Niet, Sanne Van Der; Chertkova, Anna
Taylor & Francis
DOI: 10.6084/m9.figshare.9752165.v1

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Title: The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain

Abstract

Citation Formats

Model-Based Fitting of Single-Channel Dwell-Time Distributions journal, September 2004

Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism journal, July 2002

Src-Induced Disassembly of Adherens Junctions Requires Localized Phosphorylation and Degradation of the Rac Activator Tiam1 journal, March 2009

Ferroplasma acidarmanus RPA2 Facilitates Efficient Unwinding of Forked DNA Substrates by Monomers of FacXPD Helicase journal, November 2008

Uniqueness of ab initio shape determination in small-angle scattering journal, April 2003

Protein-Associated Cation Clusters in Aqueous Arginine Solutions and Their Effects on Protein Stability and Size journal, November 2012

Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2 journal, February 2004

The Dbs PH domain contributes independently to membrane targeting and regulation of guanine nucleotide-exchange activity text, January 2006

Rac1 GTPase and the Rac1 exchange factor Tiam1 associate with Wnt-responsive promoters to enhance beta-catenin/TCF-dependent transcription in colorectal cancer cells journal, January 2008

The Dbs PH domain contributes independently to membrane targeting and regulation of guanine nucleotide-exchange activity journal, November 2006

A Modified Tandem Affinity Purification Technique Identifies That 14-3-3 Proteins Interact with Tiam1, an Interaction Which Controls Tiam1 Stability journal, December 2009

Determination of the regularization parameter in indirect-transform methods using perceptual criteria journal, August 1992

Accuracy of molecular mass determination of proteins in solution by small-angle X-ray scattering journal, February 2007

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

Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours journal, June 2002

PRIMUS: a Windows PC-based system for small-angle scattering data analysis journal, September 2003

GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors journal, February 2005

The Tiam1 PDZ Domain Couples to Syndecan1 and Promotes Cell–Matrix Adhesion journal, May 2010

ATSAS 2.1 – towards automated and web-supported small-angle scattering data analysis journal, April 2007

Structural insights into the membrane-extracted dimeric form of the ATPase TraB from the Escherichia coli pKM101 conjugation system journal, January 2011

Interaction of Rac Exchange Factors Tiam1 and Ras-GRF1 with a Scaffold for the p38 Mitogen-Activated Protein Kinase Cascade journal, June 2002

Kinetics of protein-protein association explained by Brownian dynamics computer simulation. journal, April 1992

The C-Terminal SH3 Domain Contributes to the Intramolecular Inhibition of Vav Family Proteins journal, April 2014

PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions text, January 2016

NELL2-Robo3 complex structure reveals mechanisms of receptor activation for axon guidance journal, March 2020

Realistic protein-protein association rates from a simple diffusional model neglecting long-range interactions, free energy barriers, and landscape ruggedness journal, June 2004

Single-molecule sorting of DNA helicases journal, October 2016

Regulated Membrane Localization of Tiam1, Mediated by the NH 2 -terminal Pleckstrin Homology Domain, Is Required for Rac-dependent Membrane Ruffling and C-Jun NH 2 -terminal Kinase Activation journal, April 1997

Liquid-chromatography-coupled SAXS for accurate sizing of aggregating proteins journal, June 2004

GEFs and GAPs: Critical Elements in the Control of Small G Proteins journal, June 2007

Critical Role of the Pleckstrin Homology Domain in Dbs Signaling and Growth Regulation journal, March 2003

Direct Correlation of DNA Binding and Single Protein Domain Motion via Dual Illumination Fluorescence Microscopy journal, September 2014

Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins journal, May 1994

Quantitative fluorescence labeling of aldehyde-tagged proteins for single-molecule imaging journal, April 2012

GEFs and GAPs: Critical Elements in the Control of Small G Proteins journal, July 2007

Regulating Rho GTPases and their regulators journal, June 2016

PAR-6–PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1 journal, February 2005

Quantitative Analysis of Guanine Nucleotide Exchange Factors (GEFs) as Enzymes journal, January 2013

Par-3 controls tight junction assembly through the Rac exchange factor Tiam1 journal, February 2005

The guanine nucleotide exchange factor Tiam1: A Janus-faced molecule in cellular signaling journal, March 2014

Structural Basis for Relief of Autoinhibition of the Dbl Homology Domain of Proto-Oncogene Vav by Tyrosine Phosphorylation journal, September 2000

Phosphatidylinositol 5-phosphate regulates invasion through binding and activation of Tiam1 journal, June 2014

Prognostic relevance of Tiam1 protein expression in prostate carcinomas journal, September 2006

Ras activation of a Rac1 exchange factor, Tiam1, mediates neurotrophin-3-induced Schwann cell migration journal, October 2005

Tiam1 regulates cell adhesion, migration and apoptosis in colon tumor cells journal, November 2006

Recognition and Activation of Rho GTPases by Vav1 and Vav2 Guanine Nucleotide Exchange Factors † journal, May 2005

Structural Elements, Mechanism, and Evolutionary Convergence of Rho Protein−Guanine Nucleotide Exchange Factor Complexes journal, February 2004

Advanced ensemble modelling of flexible macromolecules using X-ray solution scattering journal, February 2015

PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions journal, May 2016

Evaluating conformational free energies: The colony energy and its application to the problem of loop prediction journal, May 2002

Lysophosphatidic Acid Induces Threonine Phosphorylation of Tiam1 in Swiss 3T3 Fibroblasts via Activation of Protein Kinase C journal, December 1997

Regulation of Small GTPases by GEFs, GAPs, and GDIs journal, January 2013

Quantitative Fluorescent Labeling of Aldehyde-Tagged Proteins for Single-Molecule Imaging journal, January 2012

Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease journal, September 2013

New developments in the ATSAS program package for small-angle scattering data analysis journal, March 2012

Interaction of Arginine with Proteins and the Mechanism by Which It Inhibits Aggregation journal, October 2010

The PHCCEx domain of Tiam1/2 is a novel protein- and membrane-binding module journal, November 2009

SOLVING ION CHANNEL KINETICS WITH THE QuB SOFTWARE journal, December 2013

The guanine nucleotide exchange factor Tiam-1: a Janus-faced molecule in cellular signaling text, January 2014

RAC1: An Emerging Therapeutic Option for Targeting Cancer Angiogenesis and Metastasis journal, September 2013

Vav family exchange factors: an integrated regulatory and functional view journal, April 2014

Detecting Intramolecular Conformational Dynamics of Single Molecules in Short Distance Range with Subnanometer Sensitivity journal, December 2011

Prediction of Protein-Protein Association Rates from a Transition-State Theory journal, February 2007

Tiam1 Overexpression Potentiates Heregulin-induced Lymphoid Enhancer Factor-1/β-Catenin Nuclear Signaling in Breast Cancer Cells by Modulating the Intercellular Stability journal, April 2001

The Rac activator Tiam1 controls tight junction biogenesis in keratinocytes through binding to and activation of the Par polarity complex journal, September 2005

Ca 2+ /Calmodulin-dependent Protein Kinase II Regulates Tiam1 by Reversible Protein Phosphorylation journal, April 1999

Structure and flexibility within proteins as identified through small angle X-ray scattering journal, January 2009

A Simple Method for Improving Protein Solubility and Long-Term Stability journal, July 2004

Established and Emerging Fluorescence-Based Assays for G-Protein Function: Ras-Superfamily GTPases journal, June 2003

Allosteric Effects of the Oncogenic RasQ61L Mutant on Raf-RBD journal, March 2015

Introducing genetically encoded aldehydes into proteins journal, April 2007

Regulation of Tiam1-Rac signalling journal, April 2003

TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology journal, June 2006

High-resolution structure of the Tiam1 PH n -CC-Ex domain journal, June 2013

RHO GTPASES: Biochemistry and Biology journal, November 2005

Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease text, January 2014

Loop modeling: Sampling, filtering, and scoring journal, January 2008

Model-Based Fitting of Single-Channel Dwell-Time Distributions
journal, September 2004

Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism
journal, July 2002

Src-Induced Disassembly of Adherens Junctions Requires Localized Phosphorylation and Degradation of the Rac Activator Tiam1
journal, March 2009

Ferroplasma acidarmanus RPA2 Facilitates Efficient Unwinding of Forked DNA Substrates by Monomers of FacXPD Helicase
journal, November 2008

Uniqueness of ab initio shape determination in small-angle scattering
journal, April 2003

Protein-Associated Cation Clusters in Aqueous Arginine Solutions and Their Effects on Protein Stability and Size
journal, November 2012

Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2
journal, February 2004

The Dbs PH domain contributes independently to membrane targeting and regulation of guanine nucleotide-exchange activity
text, January 2006

Rac1 GTPase and the Rac1 exchange factor Tiam1 associate with Wnt-responsive promoters to enhance beta-catenin/TCF-dependent transcription in colorectal cancer cells
journal, January 2008

The Dbs PH domain contributes independently to membrane targeting and regulation of guanine nucleotide-exchange activity
journal, November 2006

A Modified Tandem Affinity Purification Technique Identifies That 14-3-3 Proteins Interact with Tiam1, an Interaction Which Controls Tiam1 Stability
journal, December 2009

Determination of the regularization parameter in indirect-transform methods using perceptual criteria
journal, August 1992

Accuracy of molecular mass determination of proteins in solution by small-angle X-ray scattering
journal, February 2007

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

Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours
journal, June 2002

PRIMUS: a Windows PC-based system for small-angle scattering data analysis
journal, September 2003

GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors
journal, February 2005

The Tiam1 PDZ Domain Couples to Syndecan1 and Promotes Cell–Matrix Adhesion
journal, May 2010

ATSAS 2.1 – towards automated and web-supported small-angle scattering data analysis
journal, April 2007

Structural insights into the membrane-extracted dimeric form of the ATPase TraB from the Escherichia coli pKM101 conjugation system
journal, January 2011

Interaction of Rac Exchange Factors Tiam1 and Ras-GRF1 with a Scaffold for the p38 Mitogen-Activated Protein Kinase Cascade
journal, June 2002

Kinetics of protein-protein association explained by Brownian dynamics computer simulation.
journal, April 1992

The C-Terminal SH3 Domain Contributes to the Intramolecular Inhibition of Vav Family Proteins
journal, April 2014

PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions
text, January 2016

NELL2-Robo3 complex structure reveals mechanisms of receptor activation for axon guidance
journal, March 2020

Realistic protein-protein association rates from a simple diffusional model neglecting long-range interactions, free energy barriers, and landscape ruggedness
journal, June 2004

Single-molecule sorting of DNA helicases
journal, October 2016

Regulated Membrane Localization of Tiam1, Mediated by the NH ₂ -terminal Pleckstrin Homology Domain, Is Required for Rac-dependent Membrane Ruffling and C-Jun NH ₂ -terminal Kinase Activation
journal, April 1997

Liquid-chromatography-coupled SAXS for accurate sizing of aggregating proteins
journal, June 2004

GEFs and GAPs: Critical Elements in the Control of Small G Proteins
journal, June 2007

Critical Role of the Pleckstrin Homology Domain in Dbs Signaling and Growth Regulation
journal, March 2003

Direct Correlation of DNA Binding and Single Protein Domain Motion via Dual Illumination Fluorescence Microscopy
journal, September 2014

Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins
journal, May 1994

Quantitative fluorescence labeling of aldehyde-tagged proteins for single-molecule imaging
journal, April 2012

GEFs and GAPs: Critical Elements in the Control of Small G Proteins
journal, July 2007

Regulating Rho GTPases and their regulators
journal, June 2016

PAR-6–PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1
journal, February 2005

Quantitative Analysis of Guanine Nucleotide Exchange Factors (GEFs) as Enzymes
journal, January 2013

Par-3 controls tight junction assembly through the Rac exchange factor Tiam1
journal, February 2005

The guanine nucleotide exchange factor Tiam1: A Janus-faced molecule in cellular signaling
journal, March 2014

Structural Basis for Relief of Autoinhibition of the Dbl Homology Domain of Proto-Oncogene Vav by Tyrosine Phosphorylation
journal, September 2000

Phosphatidylinositol 5-phosphate regulates invasion through binding and activation of Tiam1
journal, June 2014

Prognostic relevance of Tiam1 protein expression in prostate carcinomas
journal, September 2006

Ras activation of a Rac1 exchange factor, Tiam1, mediates neurotrophin-3-induced Schwann cell migration
journal, October 2005

Tiam1 regulates cell adhesion, migration and apoptosis in colon tumor cells
journal, November 2006

Recognition and Activation of Rho GTPases by Vav1 and Vav2 Guanine Nucleotide Exchange Factors ^†
journal, May 2005

Structural Elements, Mechanism, and Evolutionary Convergence of Rho Protein−Guanine Nucleotide Exchange Factor Complexes
journal, February 2004

Advanced ensemble modelling of flexible macromolecules using X-ray solution scattering
journal, February 2015

PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions
journal, May 2016

Evaluating conformational free energies: The colony energy and its application to the problem of loop prediction
journal, May 2002

Lysophosphatidic Acid Induces Threonine Phosphorylation of Tiam1 in Swiss 3T3 Fibroblasts via Activation of Protein Kinase C
journal, December 1997

Regulation of Small GTPases by GEFs, GAPs, and GDIs
journal, January 2013

Quantitative Fluorescent Labeling of Aldehyde-Tagged Proteins for Single-Molecule Imaging
journal, January 2012

Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease
journal, September 2013

New developments in the ATSAS program package for small-angle scattering data analysis
journal, March 2012

Interaction of Arginine with Proteins and the Mechanism by Which It Inhibits Aggregation
journal, October 2010

The PHCCEx domain of Tiam1/2 is a novel protein- and membrane-binding module
journal, November 2009

SOLVING ION CHANNEL KINETICS WITH THE QuB SOFTWARE
journal, December 2013

The guanine nucleotide exchange factor Tiam-1: a Janus-faced molecule in cellular signaling
text, January 2014

RAC1: An Emerging Therapeutic Option for Targeting Cancer Angiogenesis and Metastasis
journal, September 2013

Vav family exchange factors: an integrated regulatory and functional view
journal, April 2014

Detecting Intramolecular Conformational Dynamics of Single Molecules in Short Distance Range with Subnanometer Sensitivity
journal, December 2011

Prediction of Protein-Protein Association Rates from a Transition-State Theory
journal, February 2007

Tiam1 Overexpression Potentiates Heregulin-induced Lymphoid Enhancer Factor-1/β-Catenin Nuclear Signaling in Breast Cancer Cells by Modulating the Intercellular Stability
journal, April 2001

The Rac activator Tiam1 controls tight junction biogenesis in keratinocytes through binding to and activation of the Par polarity complex
journal, September 2005

Ca ²⁺ /Calmodulin-dependent Protein Kinase II Regulates Tiam1 by Reversible Protein Phosphorylation
journal, April 1999

Structure and flexibility within proteins as identified through small angle X-ray scattering
journal, January 2009

A Simple Method for Improving Protein Solubility and Long-Term Stability
journal, July 2004

Established and Emerging Fluorescence-Based Assays for G-Protein Function: Ras-Superfamily GTPases
journal, June 2003

Allosteric Effects of the Oncogenic RasQ61L Mutant on Raf-RBD
journal, March 2015

Introducing genetically encoded aldehydes into proteins
journal, April 2007

Regulation of Tiam1-Rac signalling
journal, April 2003

TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology
journal, June 2006

High-resolution structure of the Tiam1 PH _n -CC-Ex domain
journal, June 2013

RHO GTPASES: Biochemistry and Biology
journal, November 2005

Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease
text, January 2014

Loop modeling: Sampling, filtering, and scoring
journal, January 2008

Accurate assessment of mass, models and resolution by small-angle scattering
journal, April 2013

On the Mechanism of Trolox as Antiblinking and Antibleaching Reagent
journal, April 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