Growth and survival signals transmitted via two distinct NPXY motifs within leukocyte tyrosine kinase, an insulin receptor-related tyrosine kinase.
Leukocyte tyrosine kinase (LTK) is a receptor tyrosine kinase, which belongs to the insulin receptor family and is mainly expressed in pre-B cells and brain. In this study, we show that LTK utilizes insulin receptor substrate-1 (IRS-1) and Shc as major two substrates and possesses two NPXY motifs for them separately, tyrosine 485 of one NPXY motif at the juxtamembrane domain for IRS-1 and tyrosine 862 of another NPXY motif at the carboxyl-terminal domain for Shc. By using Ba/F3 cells expressing epidermal growth factor receptor-LTK chimeric receptors containing a mutation at each NPXY site, we showed that while both NPXY motifs equally contribute to activation of the Ras pathway and generation of mitogenic signals, only tyrosine 485 of LTK transmits cell survival signals. These data suggest that IRS-1 possesses anti-apoptotic function at least in LTK signaling. Moreover, our data indicate that the survival signaling pathway of LTK is distinct from the Ras pathway and the p70(S6) kinase pathway. Our results provide a useful insight in understanding the distinctive roles of Shc and IRS-1 in the signal transduction system of the insulin receptor family, and this anti-apoptotic function of IRS-1 may explain the survival effects of insulin, IGF-1, and interleukin 4.
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. hhirai-tky@umin.u-tokyo.ac.jp
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Ueno
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Sasaki
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Kozutsumi
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Miyagawa
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Mitani
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Yazaki
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Hirai
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000201:enzymology; D001921:Brain / Q000201:enzymology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007668:Kidney; D007700:Kinetics; D008954:Models, Biological; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010750:Phosphoproteins / Q000378:metabolism; D017354:Point Mutation; D011090:Polyenes / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D020123:Sirolimus
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D011090:Polyenes; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C489300:LTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D020123:Sirolimus