TYROSINE KINASE GROWTH-FACTOR RECEPTORS BUT NOT 7-MEMBRANE-SPANNING RECEPTORS OR PHORBOL ESTERS ACTIVATE MITOGEN-ACTIVATED PROTEIN-KINASE IN RAT HEPATOCYTES

The response of rat hepatocytes to hormones and growth factors has bee n extensively studied with respect to phospholipase regulation and cal cium mobilization, However, the mitogen-activated protein (MAP) kinase cascade which integrates signals from a wide variety of extracellular stimuli has not been examined in these cells. Thus, in the present st udy the pathways leading to activation of MAP kinase in primary cultur es of adult rat hepatocytes were investigated. Growth factors acting t hrough tyrosine kinase receptors (epidermal growth factor and hepatocy te growth factor) increased Raf and MAP kinase activity through a prot ein kinase C and calcium-independent pathway, Agonists acting through seven-membrane-spanning receptors (arginine vasopressin and angiotensi n II) increased intracellular calcium concentration but did not stimul ate Raf or MAP kinase activity. Arginine vasopressin, however, stimula ted MAP kinase activity in rat la fibroblasts transfected with the hep atic V-1a receptor and in rat aortic vascular smooth muscle cells. Pho rbol 12-myristate 13-acetate (PMA) was also unable to stimulate Raf an d MAP kinase in hepatocytes in spite of a marked activation of protein kinase C. We conclude that only signals arising from tyrosine kinase receptors are able to activate MAP kinase in hepatocytes. Neither agon ists acting through seven-membrane-spanning receptors nor phorbol este rs stimulate MAP kinase in hepatocytes. The results suggest that speci fic cellular components that link seven-membrane-spanning receptors wi th MAP kinase activation in tissues such as vascular smooth muscle are absent in rat hepatocytes.