Student #7 Response to Student #4

19 May 2005

Student7 Student7

This paper deals with cross-talk between GPCRs and RTKs, specifically looking at MOR and IR signaling. There was evidence of this cross-talk previously, and this paper demonstrates it in more detail. Treating cells with morphine reduced IR signaling to the Akt and ERK pathways. This effect was specific, as it could be inhibited by a MOR antagonist or MEK inhibitors. Using an antibody the authors generated, they was that morphine induced serine phosphorylation of the IR, and reduced the association of the IR with Shc. This disrupted formation of the IR, Shc, GRB2 signaling complex. Morphine also decreased tyrosine phosphorylation of IR at the binding sites for p85, leading to a disruption of this complex and PI3K signaling (p85 is the regulatory subunit of PI3K). Thus, MORs can affect IR signaling by disrupting 2 different signaling complexes.

I agree with student's assessment of the paper, that it demonstrates functional cross-talk between the 2 signaling pathways. It is important that the authors demonstrated their results in heterologous and native cell systems, as well as showing that it may be specific to certain areas of the brain. I also agree that the paper reinforces the importance of the formation of signaling complexes and illustrates how an independent pathway (MOR) can disrupt complexes important to another pathway (IR), thus changing the signaling ability of that pathway.