Blockade of the mitogen-activated protein (MAP) kinase pathway suppresses growth of colon cancer in vivo. Here we demonstrate a direct link between the extracellular signal-regulated kinase ERK2 and the growth-promoting cell adhesion molecule, integrin αvβ6, in colon cancer cells. Down-regulation of β6 integrin subunit expression inhibits tumour growth in vivo and MAP kinase activity in response to serum stimulation. In αvβ6-expressing cells ERK2 is bound only to the β6 subunit. The increase in cytosolic MAP kinase activity upon epidermal growth factor stimulation is all accounted for by β6-bound ERK. Deletion of the ERK2 binding site on the β6 cytoplasmic domain inhibits tumour growth and leads to an association between ERK and the β5 subunit. The physical interaction between integrin αvβ6 and ERK2 defines a novel paradigm of integrin-mediated signalling and provides a therapeutic target for cancer treatment.