Protein Growth Factors and Cytokines

As would be expected of active protein secreting cells, glandular epithelial tissue, the cytokine secreting cells of the immune system and the blood vessel endothelium, have an extensive internal structure consisting of rough endoplasmic reticulum and numerous mitochondria. Peptide hormones, growth factors and cytokines like all proteins are synthesized by DNA transcription and mRNA translation. The primary transcript of the mRNA may code for an inactive prohormone which requires careful proteolysis to produce the active hormone, as for example in the case of insulin. Adrenocorticotropic hormone (ACTH) is particularly interesting in this respect because... 

Insulins (see p. 388), growth factors, and cytokines (see p. 392), for example, act via 1-helix receptors. Binding of the signaling substance leads to activation of internal kinase activity (in some cases, dimerization of the receptor is needed for this). The activated kinase phosphorylates itself using ATP (auto-phosphorylation), and also phosphorylates tyrosine residues of other proteins (known as receptor substrates). Adaptor proteins that recognize the phosphotyrosine residues bind to the phosphorylated proteins (see pp. 388, 392). They pass the signal on to other protein kinases. 

Another important family of kinases for drug discovery is the mitogen-activated protein kinases (MAPKs). These are proline-directed serine/threonine kinases that activate their substrates by dual-phosphorylation. MAPK enzymes are activated by a variety of signals including growth factors and cytokines, discussed in chapter 6. The MAPK family plays a critical role in cell cycle progression. Small molecule inhibitors of MAPK may have utility in the treatment of cancer. 

As some of the newer drugs such as hormones, growth factors, and cytokines now being produced are peptides and certain toxins are also peptides or proteins, the role of peptidases may be important. Peptidases are especially active in the lumen of the gut, and consequently many such drugs are administered intravenously. Also some natural protein toxins may bypass the gut by via bites or stings into tissue. However, peptidase activity is also found in blood and other tissues. Peptidases are also important in the further metabolism of glutathione conjugates (see below). 

Implicated in induction and differentiation of cartilaginous tissues during development are a number of growth factors and cytokines, including the TGF-P superfamily. Those implicated include bone morphogenetic protein subfamilies, fibroblast growth factor family, insulinlike growth factor family,... 

Naturally occurring peptides, typically below the kidney size cut-off and, hence, usually collected from urine or from blood hemodialysate, provide a complementary picture of many events at the low-mass end of the plasma proteome. It provides a large source of proteins and peptides below 45 kDa. Such material has been analyzed by combined chromatography and MS approaches to resolve -5000 different peptides, including fragments of 75 different proteins [60]. Of the fragments, 55% percent were derived from plasma proteins, and 7% of the entries represented peptide hormones, growth factors, and cytokines. 

It has been known for quite some time that signalling pathways controlled by growth factors and cytokines accept signals from heptahelical receptors, coupled to heterotrimeric G proteins. However, the individual steps that funnel hormonal signals via G-protein-coupled receptors and heterotrimeric G proteins into the Ras/MAP kinase pathway were not well defined. This state of affairs has changed recently. We now have an idea, although not yet complete, how hormones may contribute to the regulation of cell proliferation via G-protein-coupled receptors. 

The c-jun gene is rapidly induced by a great variety of signals, ranging from growth factors and cytokines to lipid messengers and G proteins. >5 Each signal may result in a... 

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