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Integrins are extracellular matrix (ECM) receptors that are key players in the regulation of tumour cell invasion. The laminin-binding integrin α3β1 has previously been shown to regulate adhesion and migration of carcinoma cells in part through co-operative signalling with the tetraspanin family of transmembrane proteins. However, the spatial and temporal regulation of crosstalk between these families of transmembrane proteins in intact cells remains poorly understood. Here we have used fluorescence resonance energy transfer (FRET) to demonstrate for the first time that α3β1 and the tetraspanin CD151 directly associate at the front and retracting rear of polarised migrating breast carcinoma cells in both two-dimentional (2D) and three-dimentional (3D) matrices. Furthermore, localised α3β1–CD151 binding correlates with lower CD151 homodimerisation in cells migrating on laminin or within matrigel. Loss of α3β1 …