Receptors with protein kinase activity

See also Actions of Nitric Oxide, Receptors with Protein Kinase Activity... 

See also Hormone Action, Hormone Mechanisms of Action, Hormone Hierarchy of Action, Receptors with Protein Kinase Activity, Steroid and Thyroid Hormones - Intracellular Receptors, Action of Insulin, Action of Glucagon, Action of Epinephrine... 

See also Viral and Cellular Oncogenes, Oncogenes in Human Tumors, G Proteins and Signal Transduction, G Protein Families and Subunits, Receptors with Protein Kinase Activity, Hormone Action... 

Growth hormones, important in diabetes and cancer, activate a receptor with an intrinsic intracellular tyrosine protein kinase activity that passes on the signal by phosphorylating other proteins, often kinases themselves. To date, no specific second messengers have been associated with these systems. The amplification occurs by the turn-on of the receptor-associated protein kinase activity that can phosphorylate many proteins. 

The insulin receptor will be discussed here as a prototype of a receptor with tyrosine kinase activity which transmits a hormonal signal. The other major classes of receptors which transmit hormonal signals are the heptahelical, G-protein-coupled receptors and the nuclear receptors for steroid and non-steroid hormones (see Fig. 1.1) they are discussed later. The receptor for the peptide hormone insulin is one of the most extensively studied RTKs (receptors with tyrosine kinase activity). 

RTK. Membrane-bound receptor with tyrosine kinase activity. These receptors pass the membrane only once. On binding ligand they autophosphorylate their own tyrosine residues and form dimers. The phosphorylated tyrosine residues are recognized by intracellular proteins. Examples are growthfactor receptors. 

Dkic I, TOKIWA G, S, Courtneidge SA, SCHLESSINGER J. a role for Pyk2 and Src in linking G-protein-ooupled receptors with MAP kinase activation. Nature 383 547-SSO, 1996. 

Frizzled receptor is an example of receptors activated by the Wnt ligand. Upon activation of the Frizzled receptor, the protein kinase activity of GSK3/I is inhibited, and />-catenin is stabilized and translocates to the nucleus, where it associates with the transcription factors of the TCF family. It is not known how the activated Frizzled receptor inhibits the protein kinase activity ofGSK3/I. The protein Disshelved is involved in this downregulation. 

C. Receptors with tyrosine kinase activity Receptors Coupled to Various Cytosolic Proteins... 

Besides cytoplasmic protein kinases, membrane receptors can exert protein kinase activity. These so-called receptor tyrosine kinases (RTK) contain a ligandbinding extracellular domain, a transmembrane motif, and an intracellular catalytic domain with specificity for tyrosine residues. Upon ligand binding and subsequent receptor oligomerization, the tyrosine residues of the intracellular domain become phosphory-lated by the intrinsic tyrosine kinase activity of the receptor [3, 4]. The phosphotyrosine residues ftmction as docking sites for other proteins that will transmit the signal received by the RTK. 

The exact molecular mechanisms by which TNF-induced signal transduction are mediated remain to be characterized in detail. Oligomerization of the receptors is often followed by their phosphorylation, most likely by accessory kinases that associate with the intracellular domain of the receptor (neither receptor type displays intrinsic protein kinase activity). The existence of several phosphoproteins capable of associating with (the intracellular domain of) TNF-R55 and TNF-R75 have also been established. Following clustering of the TNF receptors, these... 

Investigations of the cellular effects of radiofrequency radiation provide evidence of damage to various types of avian and mammalian cells. These effects involve radiofrequency interactions with cell membranes, especially the plasma membrane. Effects include alterations in membrane cation transport, Na+/K+-ATPase activity, protein kinase activity, neutrophil precursor membrane receptors, firing rates and resting potentials of neurons, brain cell metabolism, DNA and RNA synthesis in glioma cells, and mitogenic effects on human lymphocytes (Cleary 1990). 

Jordan, B. A., Trapaidze, N., Gomes, I., Nivarthi, R., and Devi, L. A. (2001) Oligomerization of opioid receptors with beta 2-adrenergic receptors a role in trafficking and mitogen-activated protein kinase activation. Proc. Natl. Acad. Sci. USA 98, 343-348. 

Some water-soluble hormones bind to receptors with intrinsic protein kinase activity (often tyrosine kinases). In this case, no second messenger is required for protein kinase activation. The insulin receptor is an example of a tyrosine kinase receptor. 

These molecules span the membrane with only one a-helix. The subunits of the dimeric receptor (red and blue) each consist of two polypeptides (a and P) bound by disulfide bonds. The a-chains together bind the insulin, while the p-chains contain the transmembrane helix and, at the C-terminus, domains with tyrosine kinase activity. In the activated state, the kinase domains phosphorylate themselves and also mediator proteins (receptor substrates) that set in motion cascades of further phosphorylations (see pp. 120 and 388). 

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