IRS-1 and IRS-2 are recruited by TrkA receptor and oncogenic TRK-T1.
TRK-T1 oncogene is generated by the rearrangement of the NGF receptor TrkA with TPR. This gives rise to the constitutive tyrosine autophosphorylation and activation of the kinase. To study TRK-T1 oncogenic signaling and compare it to that induced by the genuine receptor TrkA, we investigated the involvement of IRS-1, a docking protein implicated in mitogenic signaling induced by several growth factors, in TRK-T1 and TrkA signaling. Here, we show that IRS-1 and IRS-2 are phosphorylated on tyrosine in presence of both TRK-T1 and the activated TrkA receptor. These tyrosine phosphorylations lead to IRS-1- and IRS-2-induced recruitment of p85PI3K, SHP-2, and Grb2 and increase in PI 3-kinase activity associated with IRS-1. Furthermore, we found that TRK-T1 is able to activate c-fos serum responsive element in cooperation with IRS-1 and IRS-2. We observed that TRK-T1 stimulates DNA synthesis in wild-type fibroblasts but not in IRS-1(-/-) mouse embryo fibroblasts. Yeast two-hybrid system experiments showed the occurrence of direct interaction between TRK and IRS molecules, which suggests involvement of different modes of interactions. On the whole, our results suggest that IRS-1 and IRS-2 could be substrates of TRK-T1 and TrkA, and hence could participate in their signal generation.
Miranda
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C
INSERM Unité 145 and IFR 50, Faculté de Médecine, Nice, France.
Greco
A
A
Miele
C
C
Pierotti
M A
MA
Van Obberghen
E
E
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D004247:DNA / Q000096:biosynthesis; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000378:metabolism; D051380:GRB2 Adaptor Protein; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D016716:PC12 Cells / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000502:physiology; D017434:Protein Structure, Tertiary; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051381:Rats; D020917:Receptor, trkA / Q000502:physiology*; D014018:Tissue Distribution; D014443:Tyrosine / Q000378:metabolism; D015003:Yeasts
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; C495950:Grb2 protein, rat; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; C526298:Irs2 protein, mouse; C526299:Irs2 protein, rat; D010750:Phosphoproteins; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos; D014443:Tyrosine; D004247:DNA; D020917:Receptor, trkA; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C516727:Ptpn11 protein, rat; C509248:Ptpn6 protein, mouse; C509250:Ptpn6 protein, rat