Regulated Membrane Localization of Tiam1, Mediated by the NH2-terminal Pleckstrin Homology Domain, Is Required for Rac-dependent Membrane Ruffling and C-Jun NH2-terminal Kinase Activation

doi:10.1083/jcb.137.2.387

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© The Rockefeller University Press, 0021-9525/1997//387 $5.00
The Journal of Cell Biology, Volume 137, Number 2, , 1997 387-398

Article

Regulated Membrane Localization of Tiam1, Mediated by the NH₂-terminal Pleckstrin Homology Domain, Is Required for Rac-dependent Membrane Ruffling and C-Jun NH₂-terminal Kinase Activation

Frits Michiels, Jord C. Stam, Peter L. Hordijk, Rob A. van der Kammen, Lisette Ruuls-Van Stalle, Constance A. Feltkamp, and John G. Collard

The Netherlands Cancer Institute, Antoni van Leeuwenhoekhuis, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands

Rho-like GTPases, including Cdc42, Rac, and Rho, regulate signalingpathways that control actin cytoskeletal structures and transcriptionalactivation. The Tiam1 gene encodes an activator of Rac1, andsimilarly to constitutively activated (V12)Rac1, overexpressionof Tiam1 in fibroblasts induces the formation of membrane ruffles.Tiam1 contains a Dbl homology (DH) domain and adjacent pleckstrinhomology (PH) domain, hallmarks for activators of Rho-likeGTPases. Unique for Tiam1 are an additional PH domain and a Discs-large homology region in the NH₂-terminal part of theprotein. Here we show that both in fibroblasts and COS cells,membrane localization of Tiam1 is required for the inductionof membrane ruffling. A detailed mutational analysis, in combinationwith confocal laser scanning microscopy and immunoelectronmicroscopy, demonstrates that the NH₂-terminal PH domain ofTiam1, but not the DH-adjacent PH domain, is essential for membraneassociation. This NH₂-terminal PH domain of Tiam1 can be functionallyreplaced by the myristoylated membrane localization domainof c-Src, indicating that the primary function of this PH domain is to localize the protein at the membrane. After serumstarvation, both membrane association of Tiam1 and rufflingcan be induced by serum, suggesting that receptor stimulationinduces membrane translocation of Tiam1. Similar to V12Rac1,Tiam1 stimulates the activity of the c-Jun NH₂-terminal kinase(JNK). This Rac-dependent stimulation of JNK also requires membrane association of Tiam1. We conclude that the regulatedmembrane localization of Tiam1 through its NH₂-terminal PHdomain determines the activation of distinct Rac-mediated signalingpathways.

1. Abbreviations used in this paper: aa, amino acids; DH, Dblhomology; DHR, Discs-large homology region; GDI, guanine nucleotidedissociation inhibitors; GDS, guanine nucleotide dissociationstimulator; GRF, guanine nucleotide release factor; GST, glutathioneS-transferase; HA, hemagglutinin; IP3, inositol (3,4,5)trisphosphate;JNK, c-Jun NH₂-terminal kinase; MAPK, mitogen-activated proteinkinase; PH, pleckstrin homology; PIP2 and PIP3, phosphatidylinositol(4,5)bisphosphate and (3,4,5)trisphosphate.

Address all correspondence to Dr. J.G. Collard, The NetherlandsCancer Institute, Division of Cell Biology (H1), 121 Plesmanlaan,1066 CX Amsterdam, The Netherlands. Fax: (31) 20 5121944. E-mail:JCOLL@NKI.NL

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