Hormone-activated receptor tyrosine

Insulin binding activates receptor tyrosine kinase activity and earn phorylation cascade that modulates various intracellular proteins. Fo insulin binding inhibits hormone-sensitive lipase in adipocytes. It appa so by activating a phosphatase that dephosphorylates the lipase. In adi... 

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. 

The insulin receptor (top) is a dimer with subunits that have activatable tyrosine kinase domains in the interior of the cell (see p. 224). Binding of the hormone increases the tyrosine kinase activity of the receptor, which then phosphorylates itself and other proteins (receptor substrates) at various tyrosine residues. Adaptor proteins, which conduct the signal further, bind to the phosphotyrosine residues. 

Figure 11-13 (A) A simplified version of the mitogen-activated kinase (MAPK) signaling cascade. At left is shown a hormone receptor, e.g., that for the epidermal growth factor (EGF). The receptor tyrosine kinase undergoes autophosphorylation on numerous tyrosines. The resulting phosphotyrosyl (Y-P) groups bind to SH2 domains of adapters such as Grb2 and She.

THY-R, thyroid hormone receptor TIMP, tissue inhibitor of metalloprotease TK, tyrosine kinase TLC, thin layer chromatography TLRs, Toll-like receptors TMAOX, trimethylamine oxidase TMY tobacco mosaic virus TNF, tumour necrosis factor TNF-a, tumour necrosis factor-a TNF-a-RTK, tumour necrosis factor-a receptor tyrosine kinase TOPI, DNA topoisomerase I TOPII, DNA topoisomerase II t-PA, tissue plasminogen activator TPA, 12-Tetradecanoylphorbol 13-acetate... 

Enzyme receptors are transmembrane receptors with intrinsic enzymatic activity. Examples are the receptor tyrosine kinases (RTKs), which autophosphorylate their own tyrosine residues, such as the growth factor receptors and the insulin receptor. And, finally, there are the intracellular DNA sinding receptors. They bind lipophilic ligands that pass through the membrane. They address genes directly. Examples are the steroid hormone receptors (see Chapter 11). (This figure was donated by Professor Martin Lohse, University of Wurzburg.)... 

Human growth hormone (GHl, Fig. 1), epidermal growth factor (EGF), insnlin (INS), platelet-derived growth factor (PDGF), and many cytokines bind receptors that activate intracellular tyrosine kinase activity. The major isoform of GHl is a protein of 191 amino acids (22 KDa) that fnnctions in part to stimulate the growth of bone and internal organs in children. As shown in Fig. 1, the human growth hormone receptor (GHR), which is a member of the cytokine-hematopoietin receptor superfamily. 

Figure 10 Receptor tyrosine kinase signaling process and the activation of MAP Kinase. (1) Binding of hormone to the receptor causes activation of the kinase activity of the receptor, which leads to phosphorylation of Tyr residues (2) pTyr residues recruit GRB2, which in turn recruit Sos (3) Sos promotes exchange of GTP for GDP in Ras, which leads to the active Ras-GTP complex. Then, Sos dissociates from the active Ras (4) active Ras binds to and activate the kinase Raf (4a) and hormone can dissociate from the receptor (4b) (5) activated Raf phosphoryates and activates MEK (6) activated MEK phosphorylates and activates of MAP kinase (7) activated MAP kinase can phosphorylate transcription factors (TF) and (8) phosphorylated translation factors then bind to DNA and lead to changes in gene transcription and ultimately cell division/differentiation.

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