| First Author | Miranda C | Year | 2001 |
| Journal | J Cell Physiol | Volume | 186 |
| Issue | 1 | Pages | 35-46 |
| PubMed ID | 11147812 | Mgi Jnum | J:137434 |
| Mgi Id | MGI:3799558 | Doi | 10.1002/1097-4652(200101)186:1<35::AID-JCP1003>3.0.CO;2-X |
| Citation | Miranda C, et al. (2001) IRS-1 and IRS-2 are recruited by TrkA receptor and oncogenic TRK-T1. J Cell Physiol 186(1):35-46 |
| abstractText | 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. |
