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First published online 17 February 2009
doi: 10.1242/jcs.032094

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Memo is a cofilin-interacting protein that influences PLC1 and cofilin activities, and is essential for maintaining directionality during ErbB2-induced tumor-cell migration

¹ Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland
² Terrence Donnelly Centre for Cellular and Biomolecular Research (CCBR), Department of Biochemistry and Department of Molecular Genetics, University of Toronto, Toronto, M5S 3E1, Ontario, Canada

^* Author for correspondence (e-mail: nancy.hynes{at}fmi.ch)

Accepted 19 November 2008

Heregulin (HRG) activates ErbB2-ErbB3 heterodimers thereby stimulating many cellular responses, including motility. Memo and PLC1 interact with ErbB2 autophosphorylation sites and are essential for HRG-induced chemotaxis. By tracing HRG-stimulated cell migration in Dunn chambers, we found that Memo- or PLC1 knockdown (KD) strongly impairs cell directionality. Memo has no obvious enzymatic activity and was discovered via its ability to complex with ErbB2. Using the yeast two-hybrid approach to gain insight into Memo function, an interaction between Memo and cofilin, a regulator of actin dynamics, was uncovered. The interaction was confirmed in vitro using recombinant proteins and in vivo in co-immunoprecipitation experiments where Memo was detected in complexes with cofilin, ErbB2 and PLC1. Interestingly, in Memo KD cells, HRG-induced PLC1 phosphorylation was decreased, suggesting that Memo regulates PLC1 activation. Furthermore, HRG-induced recruitment of GFP-cofilin to lamellipodia is impaired in Memo and in PLC1 KD cells, suggesting that both proteins lie upstream of cofilin in models of ErbB2-driven tumor-cell migration. Finally, in vitro F-actin binding and depolymerization assays showed that Memo enhances cofilin depolymerizing and severing activity. In summary, these data indicate that Memo also regulates actin dynamics by interacting with cofilin and enhancing its function.

Key words: Heregulin, Cofilin, Breast cancer cells, Dunn chamber assay, Transwell assay, F-actin binding and Depolymerization assays

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