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Figure 23.15: The insulin receptor and its structural relationship to other transmembrane receptors with protein tyrosine kinase activity.

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Figure 23.15: The insulin receptor and its structural relationship to other transmembrane receptors with protein tyrosine kinase activity.

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Adapted from A. Ullrich and J. Schlessinger, Cell (1990) 61:203. © 1990 Cell Press.

A tyrosine kinase is an enzyme that phosphorylates tyrosine. Generally, tyrosine kinases act upon tyrosines in other proteins, making them protein tyrosine kinases. Such enzymes play important roles in cellular signalling. The insulin receptor (Figure 23.15), for example, is a protein tyrosine kinase.

See also: Receptors with Protein Kinase Activity, Viral and Cellular Oncogenes, Oncogenes and

Cell Signalling

A number of hormone and growth factor receptors are distinctive in that they contain an intrinsic enzymatic activity and a single membrane-spanning domain. An example of this this class of receptors is the insulin receptor, for which no second messengers have yet been detected.

The insulin receptor (Figure 23. ) is a glycoprotein with an ot2^2 tetrameric structure, stabilized by disulfide bonds. Both the ot chain (735 residues) and the ft chain (620 residues) are translated from a single mRNA, giving a polypeptide chain that then undergoes proteolytic processing. The ot chain, which is thought not to span the membrane, is believed to bind insulin near its C-terminus. The ft chain has a transmembrane domain, with its C-terminus in the cell interior. The C-terminal region of the fl chain is the site of a protein tyrosine kinase activity, which is stimulated by the binding of insulin to the extracellular part of the receptor.

The kinase activity is essential to the biological activity of the insulin receptor, because some cases of non-insulin-dependent diabetes are associated with receptor mutations that abolish the kinase activity.

Given that insulin can be considered a growth factor, it is of interest that protein tyrosine kinase activity is found in other growth factor receptors, too, including the following

1. Epidermal growth factor (EGF);

2. Platelet-derived growth factor (PDGF) (Figure 23.24);

3. Colony-stimulating factor 1 (CSF-1);

4. Fibroblast growth factor (FGF); and

5. Insulin-like growth factor 1 (IGF-1).

These receptors are a family of closely related proteins (see Figure 23.15), sharing amino acid sequence homology in the domains with tyrosine kinase activity. There is evidence that the action of insulin as a growth factor is mediated through its binding to one of these receptors, the IGF-1 receptor.

Other, more distantly related membrane receptors have other enzyme activities, such as the following:

1. Proteins of the transforming growth factor ft (TGF-^) bind to a receptor that has a protein serine/threonine kinase activity (like cAMP-dependent protein kinase).

2. Atrial natriuretic factor, which controls blood volume, binds to a receptor that has both a guanylate cyclase activity and a predicted protein serine/threonine kinase activity.

See also: Second Messenger Systems, Hormone Receptors, Oncogenes and Cell Signalling, Diabetes, Action of Insulin

INTERNET LINK: Protein Kinase Classification

Figure 23.24: The intracellular portion of the dimeric (activated) PDGF J3 receptor.

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Figure 23.24: The intracellular portion of the dimeric (activated) PDGF J3 receptor.

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The complex conversion of arginine to citrulline and nitric oxide is shown in Figure 21.3. The enzyme catalyzing the reaction is nitric oxide synthase.

Nitric oxide, is involved in many signaling processes in the body. For example, it is a signal-transducing agent in the vasodilation of endothelial vascular cells and underlying smooth muscle. It is also involved in signaling decreases in blood pressure, and inhibiting platelet aggregation. In the inflammatory and immune responses, an inducible form of nitric oxide synthase produces nitric oxide at levels sufficient to be toxic to pathogenic organisms. Finally, it can act in neurotransmission in the central nervous system and stimulate erection of the penis.

Nitric oxide is a gas so it can diffuse rapidly into neighboring cells and control their metabolism. It is also unstable, with a half-life of 1 to 5 seconds, so its effects are short-lived. In the cell, nitric oxide acts primarily by stimulating cyclic GMP synthesis. The drug, Viagra, acts by inhibiting cyclic GMP breakdown, thereby prolonging the effect of nitric oxide.

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