Rac activation and inactivation control plasticity of tumor cell movement.
Tumor cells exhibit two different modes of individual cell movement. Mesenchymal-type movement is characterized by an elongated cellular morphology and requires extracellular proteolysis. In amoeboid movement, cells have a rounded morphology, are less dependent on proteases, and require high Rho-kinase signaling to drive elevated levels of actomyosin contractility. These two modes of cell movement are interconvertible. We show that mesenchymal-type movement in melanoma cells is driven by activation of the GTPase Rac through a complex containing NEDD9, a recently identified melanoma metastasis gene, and DOCK3, a Rac guanine nucleotide exchange factor. Rac signals through WAVE2 to direct mesenchymal movement and suppress amoeboid movement through decreasing actomyosin contractility. Conversely, in amoeboid movement, Rho-kinase signaling activates a Rac GAP, ARHGAP22, that suppresses mesenchymal movement by inactivating Rac. We demonstrate tight interplay between Rho and Rac in determining different modes of tumor cell movement, revealing how tumor cells switch between different modes of movement.
Sanz-Moreno
Victoria
V
Institute of Cancer Research, Cancer Research UK Centre for Cell and Molecular Biology, 237 Fulham Road, London SW3 6JB, UK.
Gadea
Gilles
G
Ahn
Jessica
J
Paterson
Hugh
H
Marra
Pierfrancesco
P
Pinner
Sophie
S
Sahai
Erik
E
Marshall
Christopher J
CJ
D000205:Actomyosin / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D020848:Chimerin 1 / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D020848:Chimerin 1; C485840:DOCK3 protein, human; D020662:Guanine Nucleotide Exchange Factors; C099942:NEDD9 protein, human; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; C120152:WASF2 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D000205:Actomyosin; D020744:rac GTP-Binding Proteins