Communication between G protein‐coupled receptor (GPCR) and epidermal growth factor receptor (EGFR) signalling systems involves cell surface proteolysis of EGF‐like precursors. The underlying mechanisms of EGFR signal transactivation pathways, however, are largely unknown. We demonstrate that in squamous cell carcinoma cells, stimulation with the GPCR agonists LPA or carbachol specifically results in metalloprotease cleavage and release of amphiregulin (AR). Moreover, AR gene silencing by siRNA or inhibition of AR biological activity by neutralizing antibodies and heparin prevents GPCR‐induced EGFR tyrosine phosphorylation, downstream mitogenic signalling events, cell proliferation, migration and activation of the survival mediator Akt/PKB. Therefore, despite some functional redundancy among EGF family ligands, the present study reveals a distinct and essential role for AR in GPCR‐triggered cellular responses. Furthermore, we present evidence that blockade of the metalloprotease‐disintegrin tumour necrosis factor‐α‐converting enzyme (TACE) by the tissue inhibitor of metalloprotease‐3, a dominant‐negative TACE mutant or RNA interference suppresses GPCR‐stimulated AR release, EGFR activation and downstream events. Thus, TACE can function as an effector of GPCR‐mediated signalling and represents a key element of the cellular receptor cross‐talk network.