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Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18517-22. doi: 10.1073/pnas.1000975107. Epub 2010 Oct 11.

ErbB2 receptor controls microtubule capture by recruiting ACF7 to the plasma membrane of migrating cells.

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1
Centre de Recherche en Cancérologie de Marseille, Institut National de la Santé et de la Recherche Médicale U891, 13009 Marseille, France.

Abstract

Microtubules (MTs) contribute to key processes during cell motility, including the regulation of focal adhesion turnover and the establishment and maintenance of cell orientation. It was previously demonstrated that the ErbB2 receptor tyrosine kinase regulated MT outgrowth to the cell cortex via a complex including Memo, the GTPase RhoA, and the formin mDia1. But the mechanism that linked this signaling module to MTs remained undefined. We report that ErbB2-induced repression of glycogen synthase kinase-3 (GSK3) activity, mediated by Memo and mDia1, is required for MT capture and stabilization. Memo-dependent inhibition of GSK3 allows the relocalization of APC (adenomatous polyposis coli) and cytoplasmic linker-associated protein 2 (CLASP2), known MT-associated proteins, to the plasma membrane and ruffles. Peripheral microtubule extension also requires expression of the plus-end binding protein EB1 and its recently described interactor, the spectraplakin ACF7. In fact, in migrating cells, ACF7 localizes to the plasma membrane and ruffles, in a Memo-, GSK3-, and APC-dependent manner. Finally, we demonstrate that ACF7 targeting to the plasma membrane is both required and sufficient for MT capture downstream of ErbB2. This function of ACF7 does not require its recently described ATPase activity. By defining the signaling pathway by which ErbB2 allows MT capture and stabilization at the cell leading edge, we provide insights into the mechanism underlying cell motility and steering.

PMID:
20937854
PMCID:
PMC2972954
DOI:
10.1073/pnas.1000975107
[Indexed for MEDLINE]
Free PMC Article

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