Some receptors cross talk with each other.

• Although for simplicity, we treated individual signaling pathways as separate sequences of events leading to separate metabolic consequences, there is in fact extensive cross talk among signaling systems.
• The regulatory circuitry that governs metabolism is richly interwoven and multilayered.
• We study the signaling pathway for insulin and epinephrine separately, but they do not operate independently.
• Insulin opposes the metabolic effects of epinephrine in most tissues, and activation of the insulin signaling pathway directly attenuates signaling through the beta-adrenergic signaling system.
• For example, the INSR kinase directly phosphorylate two Tyr residues in the cytoplasmic tail of a beta-adrenergic receptor, and PKB activated by insulin, phosphorylates two ser residues in the same region.
• Phosphorylation of these four residues triggers clathrin-aided internalization of the beta-adrenergic receptor, taking it out of service and lowering the cell's sensitivity to epinephrine.
• A second type of cross talk between these receptors occurs when phosphorylated- tyr residues on the beta-adrenergic receptor, phosphorylated by INSR, serve as nucleation points for SH2 domain- containing protein such as Grb2.
• Activation of the MAPK ERK by insulin is 5- to 10 fold greater in presence of beta-adrenergic receptor, presumably because of this cross talk.