IRS-1 and IRS-2 are recruited by TrkA receptor and oncogenic TRK-T1

TRK-T1 oncogene is generated by the rearrangement of the NCF receptor TrkA with TPR. This gives rise to the constitutive tyrosine autophosphorylation and activation of the kinase. To study TRK-T1 oncogenic signaling and compa re it to that induced by the genuine receptor TrkA, we investigated the inv olvement of IRS-1, a docking protein implicated in mitogenic signaling indu ced 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 t o IRS-1- and IRS-2-induced recruitment of P85(P13K), SHP-2, and Grb2 and in crease 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 cooperat ion 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. Ye ast two-hybrid system experiments showed the occurrence of direct interacti on between TRK and IRS molecules, which suggests involvement of different m odes 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 th eir signal generation. J. Cell. Physiol. 186:35-46, 2001. (C) 2001 Wiley-Li ss, Inc.