Tumour cells can move in two distinct ways: they can squeeze through pre-existing gaps in the extracellular matrix (ECM) as rounded, amoeboid cells, or invade tissues in an elongated, mesenchymal-type movement by degrading the ECM. Amoeboid-type motility requires actomyosin contractility that is driven by the Rho-associated, coiled-coil-containing protein kinases ROCKI and ROCKII. By contrast, mesenchymal-type invasion in melanoma is initiated by signalling pathways that involve the Crk-associated substrate (CAS) family member NEDD9, the guanine nucleotide exchange factor DOCK3 and the small GTPase Rac1. On page , Chris Marshall and colleagues now describe the molecular mechanism by which NEDD9 promotes mesenchymal and inhibits amoeboid motility. Overexpression of NEDD9 in melanoma cells changes cell morphology from rounded to elongated and enhances invasion into three-dimensional matrices. This effect requires integrin αvβ3. Furthermore, high levels of NEDD9 result in an increase in the phosphorylation of integrin β3 at Tyr785, and the formation of a signalling complex that comprises integrin β3, Src, NEDD9 and CRK. Activation of Src, subsequently, leads to the inhibition of ROCKII- and ROCKII-dependent amoeboid motility. NEDD9, thus, acts as an important signalling component that can drive the switch between the two different forms of tumour cell motility.
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