CD30 ligand signal transduction involves activation of a tyrosine kinase and of mitogen-activated protein kinase in a Hodgkin's lymphoma cell line.
CD30 is a transmembrane receptor of the nerve growth factor/tumor necrosis factor receptor superfamily. Its expression associated with Hodgkin's lymphoma and a subset of non-Hodgkin's lymphoma. Recently, its ligand (CD30L) has been cloned. CD30L enhances the proliferation of peripheral T cells and the Hodgkin's cell line HDLM-2 but seems to exert antiproliferative effects on large cell anaplastic lymphoma cell lines. Since tyrosine kinases are critical regulators of cell growth, we investigated whether CD30L induced changes in cellular tyrosine phosphorylation in CD30-positive lymphoma cell lines. Stimulation with CD30L or with an agonistic mAb against CD30, M44, induced a rapid, transient, and concentration-dependent tyrosine phosphorylation of a cytosolic protein of M(r) 42,000 (p42) in the Hodgkin's lymphomas cell line HDLM-2 but not in other CD30-positive lymphomas. In HDLM-2 cells, the phrobol ester phorbol 12-myristate 13-acetate also stimulated tyrosine phosphorylation of p42, and this effect was enhanced by M44. In marked contrast, agents stimulating the protein kinase A pathway, like forskolin or dibutyryl cAMP, did not affect tyrosine phosphorylation of P42. By immunoprecipitation with mAbs against mitogen-activated protein kinase (MAPK; p42ERKII), a M(r) 42,000 protein was identified which comigrated with p42 on SDS gels and which was phosphorylated on tyrosine residues in response to stimulation of CD30. Immune complex kinase assays showed that M44 mAb induced the activation of MAPK (p42ERKII) and the phosphorylation of a MAPK substrate, myelin basic protein. Taken together, the results suggest that CD30L induces the tyrosine phosphorylation and activation of the MAPK p42ERKII isoform in HDLM-2 cells. These findings may have implications for the understanding of the pathogenesis of Hodgkin's disease.
Wendtner
C M
CM
Ludwig-Maximilians-Universität Innenstadt, Medizinische Klinik, Munich, Germany.
Schmitt
B
B
Gruss
H J
HJ
Druker
B J
BJ
Emmerich
B
B
Goodwin
R G
RG
Hallek
M
M
D053285:CD30 Ligand; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D004789:Enzyme Activation; D006689:Hodgkin Disease / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000502:physiology*; D008970:Molecular Weight; D004676:Myelin Basic Protein / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D053285:CD30 Ligand; D008024:Ligands; D008562:Membrane Glycoproteins; D004676:Myelin Basic Protein; C505774:TNFSF8 protein, human; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013755:Tetradecanoylphorbol Acetate