Constitutive exclusion of Csk from Hck-positive membrane microdomains permits Src kinase-dependent proliferation of Theileria-transformed B lymphocytes.
Infection of bovine T cells and B cells with the intracellular protozoan parasite Theileria parva induces a transformed phenotype with characteristics comparable to leukemic cells. The transformed phenotype reverts on drug-induced parasite death, and the cured lymphocytes acquire a resting phenotype and eventually die by apoptosis if not further stimulated. Here, we show that both lymphocyte proliferation and activation of the transcription factor AP-1 are mediated by Src-family protein tyrosine kinases (PTKs) in a parasite-dependent fashion. Src-family PTKs are known to be present in glycolipid-enriched microdomains (GEMs), also called lipid rafts, and to be negatively regulated by PTK Csk complexed to tyrosine-phosphorylated transmembrane adapter protein PAG (phosphoprotein associated with GEMs) also called Cbp (Csk-binding protein). We, therefore, purified GEMs from proliferating infected B cells and from growth-arrested cells that had been drug-cured of parasites. Proliferation arrest led to a striking increase of PAG/Cbp expression; correspondingly, the amount of Csk associated with PAG/Cbp in GEMs increased markedly, whereas PTK Hck accumulation in GEM fractions did not alter on growth arrest. We propose that Theileria-induced lymphocyte proliferation and permanent activation of Hck stems from down-regulation of PAG/Cbp and the concomitant constitutive loss of the negative regulator Csk from the GEMs of transformed B cells.
Baumgartner
Martin
M
Laboratoire de Signalisation Immunoparasitaire, Département d'Immunologie, Institut Pasteur, Paris, France.
Angelisová
Pavla
P
Setterblad
Niclas
N
Mooney
Nuala
N
Werling
Dirk
D
Horejsí
Václav
V
Langsley
Gordon
G
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology; D001402:B-Lymphocytes / Q000201:enzymology / Q000469:parasitology*; D000081247:CSK Tyrosine-Protein Kinase; D002417:Cattle; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008213:Lymphocyte Activation; D021962:Membrane Microdomains / Q000201:enzymology*; D008565:Membrane Proteins / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051572:Proto-Oncogene Proteins c-hck; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D016797:Theileria parva / Q000187:drug effects / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D000981:Antiprotozoal Agents; D000081247:CSK Tyrosine-Protein Kinase; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009285:Naphthoquinones; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051572:Proto-Oncogene Proteins c-hck; D011743:Pyrimidines; D018808:Transcription Factor AP-1; D019061:src-Family Kinases; C412373:AG 1879; C046326:buparvaquone