Neurotrophic tyrosine receptor kinase

Neurotrophins are a family of related proteins that contain the following family members nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4/5. All neurotrophins are synthesized as proforms that are cleaved to release the active, mature forms. Each neurotrophin binds with high affinity to one of the tyrosine receptor kinase (trk) family of transmembrane receptors NGF to trkA, BDNF and NT-4/5 to trkB and NT-3 to trkC. The neurotrophins all act on trks that are expressed on sensory nerve terminals, the end result being enhanced sensitivity of the nociceptors. The two neurotrophins that have been most intimately linked to both injury-induced nociceptive and neuropathic pain are NGF and BDNF. 

The signaling mechanisms activated by neurotrophic factors, which include nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are fundamentally different from those discussed for G protein-coupled receptors and Ca " (Russell and Duman 2002). The neurotrophic factors bind to specific receptors, TrkA, TrkB, and TrkC (the name Trk is derived from their identification as troponin/receptor kinases from colon carcinoma) (Fig. 2). The Trk receptors contain an extracellular binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Two neurotrophic factor molecules are required for activation of a Trk receptor dimer, resulting in activation of the tyrosine kinase domains and phosphorylation of substrate proteins as well as autophosphorylation of the Trk receptor itself. 

BBB, blood brain barrier BBI, Bowman-Birk serine protease inhibitor BB-R, bombesin receptor BChE, butyryl cholinesterase BDNF, brain-derived neurotrophic factor BDNF-RTK, brain-derived neurotrophic factor receptor tyrosine kinase aBgTX, a-bungarotoxin BKAS, (3-ketoacyl-ACP synthase BK-R, bradykinin receptor BZ-R, benzodiazepine receptor... 

Iq21-q22 66.10 NTRK1 Neurotrophic tyrosine kinase, receptor, type 1 191315 Insensitivity to pain with anhidrosis, medullary thyroid carcinoma, self-mutilating behavior, mental retardation... 

Klein, R., Nanduri, V., Jing, S., Lamballe, F., Tapley, P., Bryant, S., Cordon-Cardo, C., Jones, K.R., Reichardt, L.F. and Barbacid, M. (1991) The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurtro-phin-3. Cell 66 395 03. 

BDNF (brain-derived neurotrophic factor) is a neuro-trophin, i.e. a target-derived growth factor, which is expressed in the brain predominantly in the hippocampus. It acts through its tyrosine kinase receptor, trkB,... 

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). 

Fluman studies seem to support the animal data on the role of neurotrophic factors in stress states. Depression appears to be associated with a drop in BDNF levels in the cerebrospinal fluid and serum as well as with a decrease in tyrosine kinase receptor activity. Conversely, administration of antidepressants increases BDNF levels in clinical trials and may be associated with an increase in hippocampus volume in some patients. 

Although these neurotrophic factors stimulate neurogenesis after brain ischemia, chronic intraventricular administration of peptides or proteins is inappropriate for human therapies because of insufficient penetration into brain tissue. Since various receptor tyrosine kinases, including EGF, FGF-2, BDNF, and VEGF receptors, are negatively regulated by protein tyrosine phosphatases (Ostman and Bohmer, 2001), inhibitors for protein tyrosine phosphatases possibly promote... 

The neurotrophin receptor p75 was first identified as a nerve growth factor (NGF)-binding protein and was subsequently shown to interact with each of the other neurotrophic factors, BDNF, neurotrophin-3, and neurotrophin-4/-5. It also modulates the activity of several members of the tropomyosin-related receptor tyrosine kinase family (Trk) (reviewed in Chao, 2003). p75, a member of the tumor necrosis factor superfamily, is a type I transmembrane protein with four cysteine-rich domains in its extracellular region and a Death domain in its cytoplasmic protein (Fig. 11). 

NT-3, -4, and -5 Several neurotrophic factors, including NGF Support survival of neurons NTFR Tyrosine kinase receptors, 140 kDa, RTKs A, B, C... 

---