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Rho GTPase signalling in tumour invasion

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Tumour cell migration is an essential component of invasion and metastasis. Rho-family GTPase signalling coordinates the dynamic cytoskeletal changes that are required for cell migration. To delineate Rho-family GTPase signalling in cell migration we are carrying out a systematic analysis of Rho-family GTPases their regulators and signalling pathways. Using RNA interference to target all Rho-family GTPases, guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) we have described pathways controlling two distinct forms of movement in melanoma cells. Elongated, mesenchymal-type movement is driven by Rac activation mediated by a pathway containing the adaptor protein NEDD9 and the exchange factor DOCK3 . In contrast rounded/amoeboid movement is driven by Rho and Cdc42 signalling to actomyosin contractility and suppressed by Rac activation. To investigate how Rho GTPase signalling is regulated we have studied upstream signalling events regulating the activation of Rac and actomyosin contractility. These studies reveal new insights into transmembrane signalling to Rho GTPases and demonstrate a tight interplay between Rho and Rac signalling in determining modes of cell movement.

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