TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology.
Small GTPases of the Rho family play key roles in the formation of neuronal axons and dendrites by transducing signals from guidance cues, such as neurotrophins, to the actin cytoskeleton. However, there is little insight into the mechanism by which neurotrophins regulate Rho GTPases. Here, we show the crucial role of the ubiquitous Rac1-specific guanine nucleotide exchange factor, Tiam1 (T lymphoma invasion and metastasis 1), in transducing a neurotrophin-mediated change in cell shape. We demonstrate that BDNF, acting through TrkB, directly binds and specifically activates Tiam1 by phosphorylating Tyr-829, leading to Rac1 activation and lamellipodia formation in Cos-7 cells and increased neurite outgrowth from cortical neurons. A point mutation in Tiam1, Tyr-829 to Phe-829, blocked these BDNF-induced changes in cellular morphology. The findings are evidence of a previously uncharacterized mechanism for the activation of Tiam1 and of a role for this effector in neurotrophin-mediated signal transduction leading to changes in cellular morphology.
Miyamoto
Yuki
Y
Departments of *Neurology and Neurological Sciences and yukim@nch.go.jp.|Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
Yamauchi
Junji
J
Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.|Neurobiology, Stanford University School of Medicine, Stanford, CA 94305; and.
Tanoue
Akito
A
Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
Wu
Chengbiao
C
Departments of *Neurology and Neurological Sciences and.
Mobley
William C
WC
Departments of *Neurology and Neurological Sciences and.
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D048430:Cell Shape; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism*; D011485:Protein Binding; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism*; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513259:Tiam1 protein, rat; D019000:Phosphotyrosine; D020813:Receptor, trkB; D020830:rac1 GTP-Binding Protein