Abstract
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.
Highlights
The intracellular signaling pathways of insulin receptor and insulin-like growth factor-1 (IGF-1)1 receptor have been well investigated, those of other members of insulin receptor family including leukocyte tyrosine kinase (LTK) are poorly understood
By comparing the growth of cells that express mutant chimeric receptors containing a mutation at each NPXY site, we showed that both NPXY sequences, which are binding sites for Shc and insulin receptor substrate-1 (IRS-1), contribute to activation of the Ras pathway and generation of mitogenic signals, while only tyrosine 485, which is critical for IRS-1 phosphorylation, generates cell survival signal
The epidermal growth factor receptor (EGFR)-LTK Chimeric Receptor Phosphorylates IRS-1 in a Ligand-dependent Manner, and Tyrosine 485 of LTK Is Responsible for Phosphorylation of IRS-1—Recently, it was reported that the PTB domain of IRS-1 binds to the NPXY motif encompassing tyrosine 960 of the insulin receptor [7]
Summary
The intracellular signaling pathways of insulin receptor and insulin-like growth factor-1 (IGF-1) receptor have been well investigated, those of other members of insulin receptor family including leukocyte tyrosine kinase (LTK) are poorly understood. By comparing the growth of cells that express mutant chimeric receptors containing a mutation at each NPXY site, we showed that both NPXY sequences, which are binding sites for Shc and IRS-1, contribute to activation of the Ras pathway and generation of mitogenic signals, while only tyrosine 485, which is critical for IRS-1 phosphorylation, generates cell survival signal. In this respect, at least in LTK signaling, IRS-1 is suggested to play a critical role in preventing cells from apoptotic death. Growth and Survival Signal in LTK Signaling understanding the distinctive roles of Shc and IRS-1 in the signal transduction system of the insulin receptor family
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