title: Cdc42-MRCK and Rho-ROCK signalling cooperate in myosin phosphorylation and cell invasion.
abstract: Actomyosin contractility is a mechanism by which cells exert locomotory force against their environment. 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 polarity. Tumour cells can move through a three-dimensional matrix with either a rounded morphology characterized by Rho-ROCK dependence or with an elongated morphology characterized by Rho-ROCK independence. 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.
authors.affiliation: Cancer Research UK Centre for Cell and Molecular Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Wilkinson
authors.forename: Hugh F
authors.initials: HF
authors.lastname: Paterson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Marshall
mesh_terms: D000205:Actomyosin / Q000737:chemistry; D000818:Animals; D002417:Cattle; D002465:Cell Movement; D003094:Collagen / Q000737:chemistry; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008858:Microscopy, Phase-Contrast; D009218:Myosins / Q000737:chemistry; D065636:Myotonin-Protein Kinase; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; C472645:blebbistatin; D003094:Collagen; D000205:Actomyosin; C105518:CDC42BPA protein, human; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D009218:Myosins; D020764:cdc42 GTP-Binding Protein; D020741:rho GTP-Binding Proteins