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The cell polarity regulator hScrib controls ERK activation through a KIM site-dependent interaction

Oncogene volume 29, pages 5311–5321 (2010)Cite this article

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Abstract

The cell polarity regulator, human Scribble (hScrib), is a potential tumour suppressor whose loss is a frequent event in late-stage cancer development. Little is yet known about the mode of action of hScrib, although recent reports suggest its role in the regulation of cell signalling. In this study we show that hScrib is a direct regulator of extracellular signal-regulated kinase (ERK). In human keratinocytes, loss of hScrib results in elevated phospho-ERK levels and concomitant increased nuclear translocation of phospho-ERK. We also show that hScrib interacts with ERK through two well-conserved kinase interaction motif (KIM) docking sites, both of which are also required for ERK-induced phosphorylation of hScrib on two distinct residues. Although wild-type hScrib can downregulate activation of ERK and oncogenic Ras co-transforming activity, an hScrib mutant that lacks the carboxy terminal KIM docking site has no such effects. These results provide a clear mechanistic explanation of how hScrib can regulate ERK signalling and begin to explain how loss of hScrib during cancer development can contribute to disease progression.

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Acknowledgements

This work was supported by the Yoshida (YKK) Scholarship Foundation (to KN) and by a research grant from the Associazione Italiana per la Ricerca sul Cancro (to LB). We are also very grateful to David Allen (Nextgen Sciences) for his kind support and advice on the phospho-mapping analyses.

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Authors and Affiliations

  1. International Centre for Genetic Engineering and Biotechnology, Area Science Park, Trieste, Italy

    K Nagasaka, D Pim, P Massimi, M Thomas, V Tomaić, V K Subbaiah, C Kranjec, M Myers & L Banks

  2. Department of Obstetrics and Gynecology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    K Nagasaka, S Nakagawa, T Yano & Y Taketani

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  1. K Nagasaka
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  2. D Pim
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  3. P Massimi
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  4. M Thomas
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Correspondence to K Nagasaka or L Banks.

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Nagasaka, K., Pim, D., Massimi, P. et al. The cell polarity regulator hScrib controls ERK activation through a KIM site-dependent interaction. Oncogene 29, 5311–5321 (2010). https://doi.org/10.1038/onc.2010.265

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