Receptor internalization, insulin

Biener, Y., Feinstein, R., Mayak, M., Kaburaqi, Y., Kadowaki, T. and Y. Zick, 1996, Annexin II is a novel player in insulin signal transduction. Possible association between annexin II phosphorylation and insulin receptor internalization. J. Biol. Chem. 271, 29489-29496. 

Insulin acts by binding to insulin receptors on cell membrane. The insulin receptor complex is internalized. By phosphorylation and dephosphorylation reactions there is stimulation or inhibition of enzymes involved in metabolic actions of insulin. Second messengers like phosphatidyl inositol glycan and DAG also mediate the action of insulin on metabolic enzymes. 

The bacterial chemoreceptor (Figs. 11-8 and 19-5) has a very small ligand-binding domain and a larger internal domain that activates a histidine kinase. Many growth-factor receptors, including the insulin receptor (Figs. 11-11,11-12), have internal domains with protein tyrosine kinase activity. 

Konrad, C., Kroner, A., Spiliotis, M., Zavala-Gongora, R. and Brehm, K. (2003) Identification and molecular characterisation of a gene encoding a member of the insulin receptor family in Echinococcus multiloc-ularis. International journal for Parasitology 33, 301 -312. 

The insulin receptor is internalized, and this action terminates the insulin signal at the surface of the cell. Once internalized, some of the receptors are degraded and others are recycled back to the membrane. In addition, phosphatases are able to dephosphorylate the phosphorylated insulin receptor. This dephosphorylation reduces kinase activity and decreases the responsiveness to insulin. 

A Core-Box Model for Insulin Receptor Phosphorylation and Internalization in Adipocytes... 

In an attempt to better understand the role of receptor internalization, a minimal model has been developed using hypothesis testing [10]. The model is based on experimental data on autophosphorylation of the IR. Upon addition of insulin to intact adipocytes, the IR rapidly autophosphorylates with an overshoot peak before t = 0.9 min, and then slowly declines to a quasi-steady state at around 15 min. 

A group of receptors exists that responds to so-called growth factors such as insulin, epidermal growth factor, platelet-derived growth factor, etc. These receptors have an extracellular domain that binds the growth factor and an intracellular domain that possesses latent kinase activity. The interaction of insulin, for example, results in autophosphorylation of the intracellular domain and subsequent internalization of the insulin-receptor complex. The internalized complex now possesses the properties of a tyrosine kinase and can phosphorylate cell substrates that produce the appropriate intracellular effect. However, these kinases differ from the usual protein kinases in that they phosphorylate proteins exclusively on tyrosine hydroxyl residues. The ensemble of proteins phosphorylated by the insulin receptor has not yet been identified, but there is supportive evidence that tyrosine kinase activity is required for the major actions of insulin. For example, it is possible that a membrane-linked glucose transport system becomes activated following insulin-stimulated phosphorylation. 

There is recent data to suggest that there may in fact be a biological role for the internalized insulin and EGF receptors (both of which are themselves tyrosine kinases). Thus, microinjection of insulin-occupied insulin receptors into Xenopus oocytes causes the increased phosphorylation of ribosomal protein S6 (a known substrate for the insulin receptor/kinase) [62] and the EGF receptor in endocytic vesicles has been shown to retain its kinase activity [63]. Whether the internalized insulin receptor/kinase or EGF receptor/kinase has a physiological role or not is as yet unknown. Clearly, though, these data suggest that there is much more to be learned about the role of internalized hormone-receptor complexes, especially those where the receptor possesses intrinsic enzymatic activity. 

Fig. 2. Internalization of insulin receptors and the recruitment of glucose carriers and IGF-II receptors. Occupied insulin receptors are constantly being recycled to and from the plasma membrane with a halftime of 20 min. Presumably, a very slow basal rate also occurs. Receptors can be down-regulated by degradation and up-regulated by increased synthesis. Internalization of the insulin receptor triggers glucose transporters and IGF-II receptors to be recruited to the plasma membrane in adipocytes. Whether these two proteins are in the same or different vesicles remains to be seen.

Selinger, S., Tsai, J., Pulini, M., Saperstein, A., Taylor, S. Autoimmune thrombocytopenia and primary biliary cirrhosis with hypoglycemia and insulin receptor autoantibodies. Ann. Intern. Med. 1987 107 686 - 688... 

A. Green and J.M. Olefsky, Evidence for insulin-induced internalization and degradation of insulin receptors in rat adipocytes, Proc. Natl. Acad. Sci. USA, 1982, 79, 427-431. 

---