L-selectin tyrosine phosphorylates cbl and induces association of tyrosine-phosphorylated cbl with crkl and grb2.
L-Selectin-mediated rolling of leukocytes on endothelial cells is an important step for lymphocyte homing and an early event in the immune response to pathogens or inflammatory stimuli. We have previously elucidated intracellular signaling cascades upon L-selectin engagement resulting in activation of Ras, Rac and JNK as well as cytoskeletal changes, oxygen release, ceramide synthesis and receptor capping. Activation of the src-tyrosine kinase p56lck is followed by phosphorylation of the L-selectin molecule and MAP-K. Here we show a tyrosine kinase dependent phosphorylation of the Cbl adapter protein after L-selectin engagement in lymphocytes. Phosphorylation of Cbl was absent in Jurkat cells that are pharmacologically treated with tyrosine kinase inhibitors and in lck-deficient JCaM cells. There is an activation induced association of tyrosine phosphorylated Cbl with Grb2 and CrkL, respectively, but not CrkII. Therefore, the adapter protein Cbl plays a role in L-selectin signaling and might modulate immune function by the specific recruitment of signaling molecules to multiprotein complexes.
Department of Pediatrics, Division of Neonatology, Heidelberg University, Im Neuenheimer Feld 150, Heidelberg, 69120, Germany. birgit_brenner@med.uni-heidelberg.de
B
B
Brenner
S
S
Kadel
A
A
Birle
O
O
Linderkamp
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D006801:Humans; D019169:Jurkat Cells; D019041:L-Selectin / Q000737:chemistry / Q000378:metabolism*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D050722:Oncogene Protein v-cbl; D010766:Phosphorylation; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D009687:Nuclear Proteins; D050722:Oncogene Protein v-cbl; D011506:Proteins; D015682:Retroviridae Proteins, Oncogenic; D019041:L-Selectin; D014443:Tyrosine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)