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Involvement of Janus kinases in the insulin signaling pathway
S Giorgetti-Peraldi1, F Peyrade, V Baron
1Institut National de la Santé et de la Recherche Médicale INSERM U145, Faculté de Médecine, Nice, France.
Abstract:
The adaptor molecule growth-factor-receptor-bound protein-2 (Grb2) plays a role in insulin action since it links tyrosine phosphorylated IRS-1 and Shc to the guanine-nucleotide-exchange factor, Sos, which initiates the mitogen-activated-protein (MAP) kinase cascade by producing Ras-GTP. Both IRS-1 and Shc are phosphorylated by the insulin-receptor tyrosine kinase. In the present study, we have investigated whether the tyrosine kinases of the Janus kinase family (JAK) could be involved in insulin signaling by acting on Grb2. In fibroblasts over-expressing insulin receptors we observed that two tyrosine-phosphorylated proteins interact with Grb2 and with a mutant of Grb2, which lacks the Src homology 2 (SH2) domain, indicating that these proteins associate with the SH3 domains of Grb2. Further, we found that both JAK1 and JAK2 constitutively associate with Grb2, through interaction with the SH3 domains of Grb2. Finally, insulin appears to induce the tyrosine phosphorylation of JAK1, but does not modify the tyrosine phosphorylation state of JAK2. In conclusion, our results suggest that the JAK proteins could participate in insulin signal transduction, and could therefore constitute an alternative pathway for mediating some of the pleiotropic responses induced by insulin.
Insights
Janus kinase (JAK) proteins associate with Grb2, an adaptor molecule in insulin signaling. Insulin induces JAK1 tyrosine phosphorylation, suggesting JAKs may mediate insulin
Area of Science:
- Cellular signaling
- Molecular biology
- Endocrinology
Background:
- Growth-factor-receptor-bound protein-2 (Grb2) links insulin receptor substrates to the mitogen-activated protein kinase cascade.
- Janus kinases (JAKs) are tyrosine kinases, but their role in insulin signaling is unclear.
Purpose of the Study:
- To investigate the potential involvement of JAK tyrosine kinases in insulin signal transduction.
- To determine if JAKs interact with Grb2 and are affected by insulin stimulation.
Main Methods:
- Used fibroblasts over-expressing insulin receptors.
- Investigated protein-protein interactions using Grb2 and a Grb2 mutant lacking the SH2 domain.
- Analyzed tyrosine phosphorylation states of JAK1 and JAK2 after insulin stimulation.
Main Results:
- Two tyrosine-phosphorylated proteins interacted with Grb2's SH3 domains.
- Both JAK1 and JAK2 constitutively associated with Grb2 via its SH3 domains.
- Insulin induced tyrosine phosphorylation of JAK1 but not JAK2.
Conclusions:
- JAK proteins associate with Grb2, suggesting a role in insulin signaling.
- JAKs may represent an alternative pathway for mediating insulin's diverse effects.