Trk receptors

Huang EJ, Reichardt LF (2003) Trk receptors roles in neuronal signal transduction. Ann Rev Biochem 72 609-642... 

Immunoglobulin-like cell adhesion molecules signal to the cytoplasm. In some instances, adhesion may act primarily to bind membranes to surfaces but it now seems clear that some IgCAMs act via the cytoplasmic domain after engaging with a cognate partner molecule to initiate a signal-transduction cascade as a direct consequence of an adhesive interaction. A good example of this is the Trk receptors, which have two Ig domains in their... 

Anterograde motor (kinesin) Retrograde motor (dynein) Neurotrophin (NGF, BDNF, etc.) Trk receptor Anterograde vesicle Lysosome... 

Patapoutian, A. and Reichardt, L. F. Trk receptors mediators of neurotrophin action. Curr. Opin. Neurobiol. 11 272-280, 2001. 

The neurotrophins interact with two distinct cell surface receptor species [5,6,9] (Fig. 27-2). The neurotrophins bind to the Trk family of receptors, which serve as the principal signal transducer for this class of growth factors. The Trk receptors comprise a small, highly related family of molecules that possess an extracellular ligand binding domain that selectively interacts with the individual neurotrophin species. Trk A specifically binds NGF, TrkB interacts with BDNF and NT4/5, and TrkC preferentially binds NT3. Importantly, the Trk receptors have an intracellular tyrosine kinase domain that is activated upon neurotrophin binding. The kinase domains of the Trk family members are highly conserved and the Trks differ mainly in the structure of their extracellular domains. Trk receptor expression is limited to neurons and the... 

FIGURE 2 7-2 Neurotrophin receptors. Neurotrophin family members bind specifically to cognate Trk receptors. The low affinity neurotrophin receptor, p75, promiscuously binds all neurotrophins. BDNF, brain-derived neurotrophic factor NGF, nerve growth factor NT, neurotrophin. 

Three Trks have been identified, Trk A, B and C. Ligand-binding induces Trk receptor homodimerization. This activates the intrinsic cytoplasmic tyrosine kinase activity, resulting in receptor autophosphorylation and initiation of an intracellular response. A characteristic feature of the Trk family of receptors is the presence of a leucine-rich region near the N-terminal (extracellular) end of the molecule. 

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. 

There are at least three major effector pathways that are activated by neurotrophic factor-Trk receptors. The best-characterized pathway is the extracellular-regulated kinase (ERK) cascade, which is regifiated by activation of Ras, a small membrane-bound G protein. Activation of Ras occurs when activated Trk receptor associates with adaptor proteins and a GTP exchange factor (see Russell and Duman 2002 for details). Ras in turn recruits and activates a serine threonine kinase, Raf, to the membrane resulting in the activation of ERK kinase (also referred to as MEK) and ERK (also known as mitogen activated protein kinase or MAPK). Activation of the Ras-Raf-MEK-ERK cascade can lead to regifiation of many celMar proteins, including ribosomal S6-kinase (RSK). 

A second pathway initiated by Trk receptors occurs through the direct binding of the enzyme PEC-y to an alternative phosphotyrosine residue on the Trk receptor. PEC-y, like PEC-P activated by Gq, catalyzes the formation of DAG and IP3 from PIP2. This pathway also seems to culminate in the activation of MAPK,... 

Activation of the enzyme PIS kinase (PI3K) constitutes a third pathway of Trk receptor signaling. The precise mechanism by which PI3K activation occurs has not yet been completely elucidated, but appears to involve Trk activation of intermediate proteins, such as insulin receptor substrate (IRS)-1,2 and the IRS-like protein Gabl. Downstream of PI3K activation is stimulation of the kinase Akt, which is largely responsible for the survival effects mediated by this pathway. 

The role of neurotrophins in the pathogenesis of allergic disease and asthma has been appreciated only recently. Neurotrophins are a family of growth factors that have common receptors and physiologic effects and are the principal regulators of neuronal activity, differentiation and maintenance. In humans, there are at least four defined neurotrophins also termed NGFs. These polypeptides include NGF, neurotrophin 3 (NT-3), neurotrophin 4/5 (NT-4/5) and brain-derived neurotrophic factor (BDNF). They all act on a common group of tropomyosin-related tyrosine kinase (Trk) receptors. Neurotrophin receptors are expressed in the neurons of both the central and peripheral nervous systems. 

Klein, R. L. et al. (1999). Long-term actions of vector-derived nerve growth factor or brain-derived neurotrophic factor on choline acetyltransferase and Trk receptor levels in the adult rat basal forebrain. Neuroscience 90 (3), 815-821. 

Example of Use Identification of Kinetic Proteome Changes upon Ligand Activation of Trk-Receptors... 

Peeieeer, K., Meyer, H. E., Eggert, A., Schramm, A. (2005a). Identification of dynamic proteome changes upon ligand activation of Trk-receptors using two-dimensional fluorescence difference gel electrophoresis and mass spectrometry. Mol. Cell Proteomics 4, 291-299. 

We have already alluded to the fact that the NGF-activated p75 4TR receptor is a potential death receptor, like other members of the TNF family of receptors. Evidence is now becoming available that NGF-dependent activation of p75 s can initiate ceU death and apoptosis, whereas NGF and neurotrophin-binding to TRKs (growth-factor tyrosine-kinase-type receptors) has the opposite effect and prevents cell death. Thus, early in development, endogenous NGF causes the death of neurons that express p75 4TR whereas cells that express TRK receptors are not affected and survive. Thus, the fate of developing neurons depends on the type of the receptor e3q>ressed.55 This points to the central role of programmed ceU death in the development of the nervous system.5 ... 

Yan Q, Matheson C, Sun J, Radeke MJ, Feinstein SC, Miller JA. Distribution of intracerebral ventricularly administered neurotrophins in rat brain and its correlation with trk receptor expression. Exp Neurol 1994 27 23-36. 

SWAP short wavelength automated perimedry Trk receptor tyrosine kinase... 

The neurotrophin family includes NGF, BDNF, neurotrophin-3 (NT-3), NT-4/5, and NT-6. All neurotrophins are capable of binding to the p75 receptor each neurotrophin also binds to a specific Trk receptor. Trk is the receptor for NGF TrkB is the receptor for BDNF and NT-4, while TrkC is the receptor for NT-3. Neurotrophins secreted by cells protect neurons from apoptosis (Korsching, 1993 Lewin and Barde, 1996). Similarly, ciliary neurotrophic factor (CNTF), a structurally related type I cytokine and GDNF, structurally related to TGF-[3, each constitute a sub-family of neurotrophic factors. 

The extracellular domain of Trk receptors is made up of three leucine-rich 24 residue motifs flanked on either side by a cysteine cluster (Cl is on the outer side and C2 is in the inner side), followed by two immunoglobulin (Ig)-like domains and a single transmembrane domain. The cytoplasmic domain of Trk receptors contains several tyrosine motifs (Huang and Reichardt, 2003). The major ligand binding site on Trk receptors is located in the region proximal to the Ig-... 

Binding of neurotrophins is the primary mechanism by w hich Trk receptors are activated but the affinity and specificity of neurotrophins for Trk receptors is regulated by p75 . For example, the association of p75 with Trk receptors induces a conformation that has high affinity for NGF. Association of p75 also enhances the discrimination of Trk for their preferred neurotrophin ligand (Barker, 2004 Lee et al., 2001 Meldolessi etal., 2000). 

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