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

Rho-like GTPases, including Cdc42, Rac, and Rho, regulate signaling pathways that control actin cytoskeletal structures and transcriptional activation. The Tiam1 gene encodes an activator of Rac1, and similarly to constitutively activated (V12)Rac1, overexpression of Tiam1 in fibroblasts induces the...

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Veröffentlicht in:The Journal of cell biology 1997-04, Vol.137 (2), p.387-398
Hauptverfasser: Michiels, Frits, Stam, Jord C., Hordijk, Peter L., van der Kammen, Rob A., Stalle, Lisette Ruuls-Van, Feltkamp, Constance A., Collard, John G.
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container_end_page 398
container_issue 2
container_start_page 387
container_title The Journal of cell biology
container_volume 137
creator Michiels, Frits
Stam, Jord C.
Hordijk, Peter L.
van der Kammen, Rob A.
Stalle, Lisette Ruuls-Van
Feltkamp, Constance A.
Collard, John G.
description Rho-like GTPases, including Cdc42, Rac, and Rho, regulate signaling pathways that control actin cytoskeletal structures and transcriptional activation. The Tiam1 gene encodes an activator of Rac1, and similarly to constitutively activated (V12)Rac1, overexpression of Tiam1 in fibroblasts induces the formation of membrane ruffles. Tiam1 contains a Dbl homology (DH) domain and adjacent pleckstrin homology (PH) domain, hallmarks for activators of Rho-like GTPases. Unique for Tiam1 are an additional PH domain and a Discs-large homology region in the NH2-terminal part of the protein. Here we show that both in fibroblasts and COS cells, membrane localization of Tiam1 is required for the induction of membrane ruffling. A detailed mutational analysis, in combination with confocal laser scanning microscopy and immunoelectron microscopy, demonstrates that the NH2-terminal PH domain of Tiam1, but not the DH-adjacent PH domain, is essential for membrane association. This NH2-terminal PH domain of Tiam1 can be functionally replaced by the myristoylated membrane localization domain of c-Src, indicating that the primary function of this PH domain is to localize the protein at the membrane. After serum starvation, both membrane association of Tiam1 and ruffling can be induced by serum, suggesting that receptor stimulation induces 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 regulated membrane localization of Tiam1 through its NH2-terminal PH domain determines the activation of distinct Rac-mediated signaling pathways.
doi_str_mv 10.1083/jcb.137.2.387
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The Tiam1 gene encodes an activator of Rac1, and similarly to constitutively activated (V12)Rac1, overexpression of Tiam1 in fibroblasts induces the formation of membrane ruffles. Tiam1 contains a Dbl homology (DH) domain and adjacent pleckstrin homology (PH) domain, hallmarks for activators of Rho-like GTPases. Unique for Tiam1 are an additional PH domain and a Discs-large homology region in the NH2-terminal part of the protein. Here we show that both in fibroblasts and COS cells, membrane localization of Tiam1 is required for the induction of membrane ruffling. A detailed mutational analysis, in combination with confocal laser scanning microscopy and immunoelectron microscopy, demonstrates that the NH2-terminal PH domain of Tiam1, but not the DH-adjacent PH domain, is essential for membrane association. This NH2-terminal PH domain of Tiam1 can be functionally replaced by the myristoylated membrane localization domain of c-Src, indicating that the primary function of this PH domain is to localize the protein at the membrane. After serum starvation, both membrane association of Tiam1 and ruffling can be induced by serum, suggesting that receptor stimulation induces 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 regulated membrane localization of Tiam1 through its NH2-terminal PH domain determines the activation of distinct Rac-mediated signaling pathways.</abstract><cop>United States</cop><pub>Rockefeller University Press</pub><pmid>9128250</pmid><doi>10.1083/jcb.137.2.387</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
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ispartof The Journal of cell biology, 1997-04, Vol.137 (2), p.387-398
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subjects 3T3 Cells
Actins
Animals
Blood Proteins - genetics
Calcium-Calmodulin-Dependent Protein Kinases - metabolism
Cell lines
Cell Membrane - chemistry
Cell membranes
Cells
Cellular biology
COS Cells
Cytoplasm
Drosophila Proteins
Enzyme Activation
Genes
GTP-Binding Proteins - physiology
Guanine Nucleotide Exchange Factors
Insect Proteins - genetics
JNK Mitogen-Activated Protein Kinases
Mice
Mitogen-Activated Protein Kinases
NIH 3T3 cells
P branes
Phenotypes
Phosphoproteins
Proteins - analysis
Proteins - genetics
Proto-Oncogene Proteins pp60(c-src) - genetics
rac GTP-Binding Proteins
Recombinant Fusion Proteins
Ruffles
Sequence Deletion
Sequence Homology, Amino Acid
Signal Transduction - physiology
T-Lymphoma Invasion and Metastasis-inducing Protein 1
Tumor Suppressor Proteins
title 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
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