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PMID: 10998360 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Regulation of the Rac1-specific exchange factor Tiam1 involves both phosphoinositide 3-kinase-dependent and -independent components.

The Biochemical journal ·Vol. 351 ·No. Pt 1 ·2000-10-01 ·Pages 173-82

Fleming IN, Gray A, Downes CP

Abstract

The small GTPase Rac1 is involved in regulating membrane ruffling, gene transcription, cell-cycle progression and cell transformation, and some of these events are blocked by inhibitors of phosphoinositide 3-kinase (PI 3-kinase). Moreover, Rac1 can be activated by several guanine nucleotide exchange factors, which facilitate the release of GDP. We therefore investigated the ability of PI 3-kinase lipid products to regulate Tiam1, a Rac1-specific exchange factor. Tiam1 bound to polyphosphorylated inositol lipids in the rank order PtdIns(3,4,5)P(3)>PtdIns(3,4)P(2) >>PtdIns(4,5)P(2), and this binding could be attributed to the N-terminal pleckstrin-homology (N-PH) domain. Both PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2) enhanced Tiam1 guanine nucleotide exchange activity in vitro, but PtdIns(4,5)P(2) had no effect. Co-expression of a constitutively active PI 3-kinase with Tiam1 increased the amount of GTP-bound Rac1 in vivo, a response which required the N-PH domain of Tiam1. Ectopic expression of Tiam1 caused membrane ruffling in Swiss 3T3 cells that was characterized by wortmannin-sensitive and -insensitive components, which required the N-PH domain and the C-terminal PH domain of Tiam1 respectively. These results reveal novel facets of Tiam1-dependent regulation of Rac1 function.

MeSH Terms
Androstadienes/pharmacology Animals Blood Proteins/chemistry Cell Line Cell Membrane/drug effects,metabolism Enzyme Activation/drug effects Guanine Nucleotide Exchange Factors Guanosine Diphosphate/metabolism Guanosine Triphosphate/metabolism Humans Mice Mutation/genetics Phosphatidylinositol 3-Kinases/metabolism Phosphatidylinositols/metabolism Phosphoinositide-3 Kinase Inhibitors Phosphoproteins/chemistry Protein Binding Protein Structure, Tertiary Proteins/chemistry,genetics,metabolism Sequence Homology, Amino Acid Substrate Specificity T-Lymphoma Invasion and Metastasis-inducing Protein 1 Wortmannin rac1 GTP-Binding Protein/metabolism
Chemicals
Androstadienes Blood Proteins Guanine Nucleotide Exchange Factors Phosphatidylinositols Phosphoinositide-3 Kinase Inhibitors Phosphoproteins Proteins T-Lymphoma Invasion and Metastasis-inducing Protein 1 TIAM1 protein, human Tiam1 protein, mouse platelet protein P47 Guanosine Diphosphate Guanosine Triphosphate rac1 GTP-Binding Protein Wortmannin
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Fleming I N
Department of Biochemistry, Medical Sciences Institute, University of Dundee, Dundee DD1 5EH, Scotland, UK. I.N.Fleming@Dundee.ac.uk
Gray A
Downes C P
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Article Info
Journal
The Biochemical journal
Abbr.
Biochem J
ISSN
0264-6021
DOI
10.1042/0264-6021:3510173
Email
i.n.fleming@dundee.ac.uk
Published
2000-10-01
Pages
173-82
Language
English
Region
England
NLM ID
2984726R
PMCID
PMC1221348
Subset
IM
External Links
PubMed source DOI: 10.1042/0264-6021:3510173 PMC Full Text View journal details
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