CD30 LIGAND SIGNAL-TRANSDUCTION INVOLVES ACTIVATION OF A TYROSINE KINASE AND OF MITOGEN-ACTIVATED PROTEIN-KINASE IN A HODGKINS LYMPHOMA CELL-LINE

CD30 is a transmembrane receptor of the nerve growth factor/tumor necr osis factor receptor superfamily. Its expression is associated with Ho dgkin's lymphoma and a subset of non-Hodgkin's lymphoma. Recently, its ligand (CD30L) has been cloned. CD30L enhances the proliferation of p eripheral T cells and the Hodgkin's cell line HDLM-2 but seems to exer t antiproliferative effects on large cell anaplastic lymphoma cell lin es. Since tyrosine kinases are critical regulators of cell growth, we investigated,whether CD30L induced changes in cellular tyrosine phosph orylation in CD30-positive lymphoma cell lines. Stimulation with CD30L or with an agonistic mAb against CD30, M44, induced a rapid, transien t, and concentration-dependent tyrosine phosphorylation of a cytosolic protein of M(r) 42,000 (p12) in the Hodgkin's lymphoma cell line HDLM -2 but not in other CD30-positive lymphomas. In HDLM-2 cells, the phor bol ester phorbol 12-myristate 13-acetate also stimulated tyrosine pho sphorylation of p12, and this effect was enhanced by M44. In marked co ntrast, agents stimulating the protein kinase A pathway, like forskoli n or dibutyryl cAMP, did not affect tyrosine phosphorylation of p42. B y immunoprecipitation with mAbs against mitogen-activated protein kina se (MAPK; p42(ERKII)), a M(r) 42,000 protein was identified which comi grated with p42 on SDS gels and which was phosphorylated on tyrosine r esidues in response to stimulation of CD30. Immune complex kinase assa ys showed that M44 mAb induced the activation of MAPK (p42(ERKII)) and the phosphorylation of a MAPK substrate, myelin basic protein. Taken together, the results suggest that CD30L induces the tyrosine phosphor ylation and activation of the MAPK p42(ERKII) isoform in HDLM-2 cells. These findings may have implications for the understanding of the pat hogenesis of Hodgkin's disease.