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Cdc42–MRCK and Rho–ROCK signalling cooperate in myosin phosphorylation and cell invasion

Nature Cell Biology volume 7, pages 255–261 (2005)Cite this article

Abstract

Actomyosin contractility is a mechanism by which cells exert locomotory force against their environment1. Signalling downstream of the small GTPase Rho increases contractility through Rho-kinase (ROCK)-mediated regulation of myosin-II light chain (MLC2) phosphorylation. Cdc42 signalling has been shown to control cell polarity2. Tumour cells can move through a three-dimensional matrix with either a rounded morphology3,4 characterized by Rho–ROCK dependence5 or with an elongated morphology3,4 characterized by Rho–ROCK independence5. Here we show that contractility necessary for elongated morphology and invasion can be generated by Cdc42–MRCK signalling. MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) cooperates with ROCK in the maintenance of elongated morphology and invasion and either MRCK or ROCK is sufficient for MLC2 phosphorylation, through the inhibitory phosphorylation of myosin phosphatase. By contrast, in rounded ROCK-dependent movement, where MLC2 phosphorylation is higher, MRCK has a smaller role. Our data show that a Cdc42–MRCK signal mediates myosin-dependent cell motility and highlight convergence between Rho and Cdc42 signalling.

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Figure 1: BE cell invasion requires myosin contractility, MRCK or ROCK.
Figure 2: Elongated morphology requires myosin contractility, MRCK or ROCK.
Figure 4: Rounded morphology requires high MRCK- or ROCK-driven contractility.
Figure 3: MLC2 and MYPT1 phosphorylation require MRCK or ROCK.

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Acknowledgements

We thank T. Leung for generous gifts of reagents, A. Klippel for the gift of anti-PKN3 antiserum, C. MacKintosh for the gift of microcystin-LR, J. Metcalfe for peptide synthesis, and A. Hall, J. Rosenblatt and E. Sahai for helpful discussion. S.W. is funded by an Institute of Cancer Research studentship. C.J.M. is a Gibb Life Fellow of Cancer Research UK. Work in C.J.M.'s laboratory is supported by Cancer Research UK.

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  1. Cancer Research UK Centre for Cell and Molecular Biology, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK

    Simon Wilkinson, Hugh F. Paterson & Christopher J. Marshall

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Correspondence to Christopher J. Marshall.

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Wilkinson, S., Paterson, H. & Marshall, C. Cdc42–MRCK and Rho–ROCK signalling cooperate in myosin phosphorylation and cell invasion. Nat Cell Biol 7, 255–261 (2005). https://doi.org/10.1038/ncb1230

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