AGONISTIC MONOCLONAL-ANTIBODIES AGAINST THE MET RECEPTOR DISSECT THE BIOLOGICAL RESPONSES TO HGF

Hepatocyte growth factor, also known as scatter factor, is a pleiotrop ic cytokine, which stimulates cell motility, invasion, proliferation, survival and morphogenesis, and induces the expression of specific gen es by activating its receptor tyrosine kinase, In this work we have is olated, characterized and used as agonists two monoclonal antibodies ( mAbs) directed against the extracellular domain of HGF receptor to inv estigate the requirements for receptor activation and for the differen t biological responses, The two mAbs display similar affinities, react with epitopes different from the hepatocyte growth factor binding sit e, and behave as either full or partial agonists, The full agonist mAb (DO-24) triggers all the biological effects elicited by hepatocyte gr owth factor, namely motility, proliferation, cell survival, invasion, tubulogenesis and angiogenesis, The partial agonist mAb (DN-30) induce s only motility, Only the full agonist mAb is able to induce and susta in the expression of urokinase-type plasminogen activator receptor for prolonged periods of time, while both mAbs up-regulate the constituti ve expression of urokinase-type plasminogen activator, Both mAbs activ ate receptor phosphorylation, which, being strictly dependent on mAb b ivalence, requires receptor dimerization, Since simple receptor dimeri zation is not sufficient to trigger full biological responses, we prop ose that the region on the beta chain of the receptor recognized by th e full agonist mAb is crucial for optimal receptor activation.