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Memo mediates ErbB2-driven cell motility


Clinical studies have revealed that cancer patients whose tumours have increased ErbB2 expression tend to have more aggressive, metastatic disease, which is associated with parameters predicting a poor outcome1,2. The molecular basis underlying ErbB2-dependent cell motility and metastases formation, however, still remains poorly understood. In this study, we show that activation of a set of signalling molecules, including MAPK, phosphatidylinositol-3-OH kinase (PI(3)K) and Src, is required for Neu/ErbB2-dependent lamellipodia formation and for motility of breast carcinoma cells. Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of Neu/ErbB2 phosphorylation at Tyr 1201 or Tyr 1227. We describe a novel molecule, Memo (mediator of ErbB2-driven cell motility), that interacts with a phospho-Tyr 1227-containing peptide, most probably through the Shc adaptor protein. After Neu/ErbB2 activation, Memo-defective cells form actin fibres and grow lamellipodia, but fail to extend microtubules towards the cell cortex. Our data suggest that Memo controls cell migration by relaying extracellular chemotactic signals to the microtubule cytoskeleton.

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Figure 1: Tyr 1201 (YC) and Tyr 1227 (YD) are required for HRG-induced cell migration.
Figure 2: Activition of MAPK, PI(3)K and p38-MAPK is not sufficient for Neu/ErbB2-driven cell migration.
Figure 3: Memo interacts with ErbB2 Tyr 1227 through the Shc adaptor molecule.
Figure 4: Memo is required for ErbB2-driven cell motility, but not for lamellipodia formation.
Figure 5: Memo is required for ErbB2-dependent microtubule outgrowth.

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We thank F. Maurer and S. Lienhard for technical assistance, D. Cappellen for help with quantitative PCR and discussions, S. Kleiner for help with siRNA experiments, A. Brahmbhatt and R. Klemke for help with lamellipodia purification, W. Krek, G. Thomas and R. Chiquet for critical reading of the manuscript. This work was supported by the Novartis Research Foundation and grants from the Swiss Cancer League to A.B. and R.M.

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Correspondence to Nancy E. Hynes.

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Marone, R., Hess, D., Dankort, D. et al. Memo mediates ErbB2-driven cell motility. Nat Cell Biol 6, 515–522 (2004).

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