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Published online April 21, 2008
doi:10.1083/jcb.200709033
The Journal of Cell Biology, Vol. 181, No. 2, 351-365
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Yamauchi et al.
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Article

ErbB2 directly activates the exchange factor Dock7 to promote Schwann cell migration



Junji Yamauchi1, Yuki Miyamoto1, Jonah R. Chan2, and Akito Tanoue1

1 Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan
2 Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033

Correspondence to Junji Yamauchi: jyamauchi{at}nch.go.jp; or Jonah R. Chan: jonah.chan{at}usc.edu

The cellular events that precede myelination in the peripheral nervous system require rapid and dynamic morphological changes in the Schwann cell. These events are thought to be mainly controlled by axonal signals. But how signals on the axons are coordinately organized and transduced to promote proliferation, migration, radial sorting, and myelination is unknown. We describe that the axonal signal neuregulin-1 (NRG1) controls Schwann cell migration via activation of the atypical Dock180-related guanine nucleotide exchange factor (GEF) Dock7 and subsequent activation of the Rho guanine triphosphatases (GTPases) Rac1 and Cdc42 and the downstream c-Jun N-terminal kinase. We show that the NRG1 receptor ErbB2 directly binds and activates Dock7 by phosphorylating Tyr-1118. Dock7 knockdown, or expression of Dock7 harboring the Tyr-1118–to–Phe mutation in Schwann cells, attenuates the effects of NRG1. Thus, Dock7 functions as an intracellular substrate for ErbB2 to promote Schwann cell migration. This provides an unanticipated mechanism through which ligand-dependent tyrosine phosphorylation can trigger the activation of Rho GTPase-GEFs of the Dock180 family.

Abbreviations used in this paper: ANOVA, analysis of variance; CRIB, Cdc42/Rac interactive binding domain; DH, Dbl homology; DHR, Dock homology region; DRG, dorsal root ganglion; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; IGF, insulin-like growth factor; MAP, microtubule-associated protein; NRG1, neuregulin-1; NT3, neurotrophin-3; PH, pleckstrin homology; SH, Src homology; WASP, Wiskott-Aldrich syndrome protein.


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