l-Selectin activates the Ras pathway via the tyrosine kinase p56lck
B Brenner, E Gulbins, K Schlottmann… - Proceedings of the …, 1996 - National Acad Sciences
B Brenner, E Gulbins, K Schlottmann, U Koppenhoefer, GL Busch, B Walzog, M Steinhausen…
Proceedings of the National Academy of Sciences, 1996•National Acad SciencesSelectins mediate rolling, the initial step of leukocyte adhesion to endothelial cells [Springer,
TA (1995) Annu. Rev. Physiol. 57, 827–872 and Butcher, EC (1991) Cell 67, 1033–1036]. In
this study we show that l-selectin triggering of Jurkat cells using different antibodies or
glycomimetics resulted in activation of the src-tyrosine kinase p56lck; tyrosine
phosphorylation of intracellular proteins, in particular mitogen-activating protein kinase and l-
selectin; and association of Grb2/Sos with l-selectin. This association correlated with an …
TA (1995) Annu. Rev. Physiol. 57, 827–872 and Butcher, EC (1991) Cell 67, 1033–1036]. In
this study we show that l-selectin triggering of Jurkat cells using different antibodies or
glycomimetics resulted in activation of the src-tyrosine kinase p56lck; tyrosine
phosphorylation of intracellular proteins, in particular mitogen-activating protein kinase and l-
selectin; and association of Grb2/Sos with l-selectin. This association correlated with an …
Selectins mediate rolling, the initial step of leukocyte adhesion to endothelial cells [Springer, T. A. (1995) Annu. Rev. Physiol. 57, 827–872 and Butcher, E. C. (1991) Cell 67, 1033–1036]. In this study we show that l-selectin triggering of Jurkat cells using different antibodies or glycomimetics resulted in activation of the src-tyrosine kinase p56lck; tyrosine phosphorylation of intracellular proteins, in particular mitogen-activating protein kinase and l-selectin; and association of Grb2/Sos with l-selectin. This association correlated with an activation of p21Ras, mitogen-activating protein kinase, Rac2, and a transient increase of O2− synthesis. Stimulation of the Ras pathway by l-selectin requires functional p56lck, since p56lck-deficient Jurkat cells (JCaM1.6) do not show tyrosine phosphorylation, association of l-selectin with Grb2/Sos, and activation of Ras upon l-selectin triggering. Transfection of JCaM1.6 cells with p56lck reconstitutes the observed signaling events. Genetic inhibition of Ras or Rac2 prevented Rac2 stimulation and O2− synthesis, respectively. The specificity and the physiological significance of the observed signaling cascade is indicated by stimulation of l-selectin-transfected P815, l-selectin-positive CEM or peripheral blood lymphocytes resulting in the same activation events as in Jurkat cells. Our results point to a signaling cascade from l-selectin via p56lck, Grb2/Sos, Ras, and Rac2 to O2− .
National Acad Sciences