The growth of melanocytes, the pigment-producing cells of the skin, normally is restricted to the epidermis. Transformed melanocytes, which have invaded the dermis, however, have gained the ability to grow in this new environment and to counteract apoptosis induced by the dermal connective tissue. The expression of genes contributing to the survival of melanocytes in the dermal environment, therefore, might be involved in melanoma development. Using a differential display approach, we identified osteopontin as such a gene. In melanocytes, expression of the secreted adhesion protein OPN was up-regulated by the melanoma-inducing receptor tyrosine kinase Xmrk as well as by the fibroblast growth factor receptor, which plays a decisive role in human melanoma. Activation of both receptors triggered survival of melanocytes in three-dimensional dermal collagen gels. Competition experiments revealed that the presence of OPN in the medium as a result of receptor signaling was contributing to these effects. Addition of exogenous OPN allowed melanocytes to adhere, spread, and survive in three-dimensional collagen gels, whereas in the absence of OPN, the cells underwent apoptosis. The integrin alpha(v)beta(3) known to be involved in melanoma cell survival and growth was identified as an OPN receptor, which points to an OPN-mediated cross-talk between growth factor receptors and this integrin receptor in melanocytes. In summary, we could show that in melanocytes growth factor receptor-induced secretion of OPN can promote antiapoptotic signaling and mediate appropriate interactions with the extracellular matrix in an autocrine way. Our findings suggest a new role of growth factor receptors of the family of receptor tyrosine kinases in processes associated with melanoma development and progression.