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Prepublished online as a Blood First Edition Paper on October 31, 2002; DOI 10.1182/blood-2002-02-0456.
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Blood, 1 March 2003, Vol. 101, No. 5, pp. 1874-1881
IMMUNOBIOLOGY
Constitutive exclusion of Csk from Hck-positive membrane
microdomains permits Src kinase-dependent proliferation of
Theileria-transformed B lymphocytes
Martin Baumgartner,
Pavla Angelisová,
Niclas Setterblad,
Nuala Mooney,
Dirk Werling,
Václav Horejsí, and
Gordon Langsley
From the Laboratoire de Signalisation
Immunoparasitaire, Département d'Immunologie, Institut Pasteur,
Paris, France; Institute of Molecular Genetics, Prague,
Czech Republic; Institut National de la Santé et de la Recherche
Médicale (INSERM) U396, Immunogénetique Humaine, Institut
des Cordeliers, Paris, France; and Institute of Veterinary
Virology Faculty of Veterinary Medicine, Bern, Switzerland.
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.
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