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biopharmaceuticals biochemistry and biotecnology - Walsh G.

Walsh G. biopharmaceuticals biochemistry and biotecnology - John Wiley & Sons, 2003. - 572 p.
ISBN 0-470-84327-6
Download (direct link): biochemistryandbiotechnology2003.pdf
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The TGF-bs exert their biological actions by binding to specific receptors, of which there are three types (I, II and III). All are transmembrane glycoproteins. All three TGF-bs bind to all three receptor types, although they bind with higher affinity to types I and II receptors (53 kDa and 65 kDa, respectively). The intracellular domains of the type I and II receptors display endogenous serine/threonine protein kinase activity.
The larger (829 amino acid) type III receptor is a proteoglycan (a class of very highly glycosylated acidic glycoprotein). Also known as b-glycan, it is characterized by a short cytoplasmic domain and displays no capability of transducing signals. The type III receptor (which is less widely distributed than the others) may function to concentrate ligand and present it to type I and II receptors. The exact molecular events underlining TGF signal transduction remain to be elucidated, although co-expression of type I and II receptors appears to be a necessary prerequisite. This has led to speculation that active signal transduction requires ligand-induced formation of a hetromeric complex containing both type I and II receptor units. A family of cytoplasmic proteins, Smad proteins, are also known to transiently associate with activated TGF-b receptors. Interaction results in the activation via phosphorylation of the Smads, which then translocate to the nucleas. Here they function as transcriptional activators of various genes.
NEUROTROPHIC FACTORS
Neurotrophic factors constitute a group of cytokines that regulate the development, maintenance and survival of neurons in both the central and peripheral nervous systems (Table 7.9). While the first member of this family (nerve growth factor, NGF) was discovered more than 50 years ago, it is only in the last decade that the other members have been identified and characterized. The major sub-family of neurotrophic factors are the neurotrophins.
The original understanding of the term ‘neurotrophic factor’ was that of a soluble agent found in limiting quantities in the environment of sensitive neurons, and being generally
294 BIOPHARMACEUTICALS
Table 7.9. Molecules displaying neurotrophic activity in vivo and/ or with neurons in culture
Nerve growth factor (NGF)
Brain-derived neurotrophic factor (BDNF)
Neurotrophin 3 (NT-3)
Neurotrophin 4/5 (NT-4/5)
Neurotrophin 6 (NT-6)
Ciliary neurotrophic factor (CNTF)
Glial cell-line-derived neurotrophic factor (GDNF)
Fibroblast growth factors (FGFs)
Platelet-derived growth factor (PDGF)
Insulin-like growth factors 1 and 2 (IGFs 1 and 2) Transforming growth factor b1 (TGF-b1) Granulocyte-macrophage colony-stimulating factor (GM-CSF) Erythropoietin (EPO)
Leukaemia inhibitory factor (LIF)
manufactured by the neuronal target cells. It specifically promoted the growth and maintenance of those neurons (see also Box 7.1). This description is now considered to be oversimplistic. Many neurotrophic factors are also synthesized by non-nerve target cells and influence cells other than neurons (e.g. NGF is synthesized by mast cells and influences various cells of the immune system). Furthermore, various cytokines (including several growth factors; Table 7.9), discovered because of their ability to stimulate the growth of non-neuronal cells, are now also known to influence neuronal cells.
Each neurotrophic factor influences the growth and development of a specific group of neuronal types, with some cells being sensitive to several such factors. Many sustain specific neuronal populations whose death underlines various neurodegenerative diseases. This raises the possibility that these regulatory molecules may be of benefit in treating such diseases. Results from early clinical trials have been mixed, but many remain optimistic that neurotrophic factors may provide future effective treatments for some currently incurable neurodegenerative conditions.
The neurotrophins
The neurotrophins are a group of neurotrophic factors which all belong to the same gene family. They include NGF, as well as brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin 4/5 (NT-4/5) and neurotrophin-6 (NT-6). All are small, basic proteins sharing approximately 50% amino acid homology. They exist mainly as homodimers and promote signal transduction by binding to a member of the Trk family of tyrosine kinase receptors (Table 7.10).
NGF is the prototypic neurotrophin. The mature NGF polypeptide contains 120 amino acids, exhibits a molecular mass of 26 kDa and a pI of approximately 10. It contains three intra-chain disulphide linkages, which are essential for activity. NGF is synthesized and released from target tissues of sympathetic neurons and cholinergic basal forebrain neurons. It is also synthesized by non-neuronal tissue, including salivary glands, the prostate and mast cells. It functions to
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