Differential signaling to glycogen synthesis by the intracellular domain of the insulin versus the insulin-like growth factor-1 receptor. Evidence from studies of TrkC-chimeras.
Insulin and insulin-like growth factor-1 (IGF-1) have similar cell-surface receptors yet subserve different physiological functions. To examine whether these differences relate to intrinsic signaling properties of the intracellular domains of their respective receptors, chimeric receptors were constructed using the extracellular domain of the neurotrophin-3 (NT-3) receptor, TrkC, and the intracellular domain of either the insulin receptor or the IGF-1 receptor. TrkC-IR (TIR) and TrkC-IGF-1R (TIGR) were stably expressed in 3T3-L1 cells. While TIR and TIGR cell lines expressing similar numbers of chimeric receptors showed a similar dose-response relationship in NT-3 stimulated DNA synthesis, NT-3 stimulated glycogen synthesis was greater in TIR than in TIGR cells (maximum TIGR response was 35% of maximum TIR response). Additionally, the concentration of NT-3 at which significant stimulation of glycogen synthesis was seen was 0.1 ng/ml in TIR and 1 ng/ml in TIGR cells. Basal levels of thymidine incorporation but not glycogen synthesis were consistently higher in TIR than in TIGR expressing cells. No detectable basal autophosphorylation of chimeric receptors was seen in any of the cell lines. However, exposure of cell lines to the phosphatase inhibitor bisperoxovanadate resulted in greater basal autophosphorylation of the TIR and endogenous murine IR than the TIGR and endogenous murine IGF-1R. Thus, in this system, the intracellular domain of the IR appears to couple more effectively to glycogen synthesis than that of the IGF-1R, whereas the intracellular domains of both receptors have a similar capacity to stimulate DNA synthesis.
Kalloo-Hosein
H E
HE
University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QR United Kingdom.
Whitehead
J P
JP
Soos
M
M
Tavaré
J M
JM
Siddle
K
K
O'Rahilly
S
S
D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D006003:Glycogen / Q000096:biosynthesis*; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D007328:Insulin; D017475:Receptors, Nerve Growth Factor; D011993:Recombinant Fusion Proteins; D006003:Glycogen; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D020812:Receptor, trkC