T-lymphocyte proliferation: tyrosine kinases in interleukin 2 signal transduction.
Interleukin 2 (IL-2)-induced tyrosine phosphorylation appears to play a major role in IL-2-induced cellular proliferation. Several intracellular substrates including the beta chain of the IL-2 receptor complex (IL-2R beta), raf, MAP2 kinase, the regulatory 83 kDa subunit of phosphatidylinositol-3 kinase and S6 kinases are substrates for the IL-2 receptor activated kinase(s). However, none of the identified members of the IL-2 receptor complex exhibits intrinsic tyrosine kinase activity. Therefore, the IL-2R complex must activate intracellular tyrosine kinases. We have demonstrated that specific tyrosine and serine/threonine kinases are coprecipitated with IL-2 receptor constructs that mediate IL-2-induced cell proliferation but not with those that do not. The IL-2-activated tyrosine kinase appears to be associated with a serine and proline rich intracellular domain which is highly conserved between IL-2R beta and the erythropoietin receptor. Although the responsible kinase has not been identified, lck, fyn, fgr, ltk, hck and lyn can be ruled out as obligatory mediators. Using methods to clone tyrosine kinases from T cells, we have identified potential candidate kinases, including several which had not been known to be expressed by T lymphocytes as well as several unique kinases which had not been previously identified in any cell type.
Schmandt
R
R
Fung
M
M
Arima
N
N
Zhang
N
N
Leung
B
B
May
C
C
Gibson
S
S
Hill
M
M
Green
W
W
Mills
G B
GB
D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003001:Cloning, Molecular; D016384:Consensus Sequence; D004705:Endocytosis; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000145:classification / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D015854:Up-Regulation
D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases