Trk receptor signaling

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). 

The activation of p75 plays an important role in neuronal growth. Unliganded p75 is an activator of RhoA which mediates the effects of CNS-derived myelin-based growth 

Neurons communicate with each other (as well as with other non-neural cells) either via electrical (action potential) or 

What is renovating in your brain right now as you are learning about signaling of memory formation, a fraction of which you vdll perhaps retain in your memory for years to come The answer is neuronal plasticity, the key prelude to memory formation. It is a consequence of both, qualitative alteration in efficacy of synaptic transmission and quantitative alteration in synapse number due to synaptic growth. 

Neurotrophin-Trk receptor complexes are internalized and retrogradely transported from distal axons to the neuronal cell body where they signal to the soma to mediate target-dependent survival, growth and gene expression. The neurotrophin-Trk receptor complex is internalized by four mechanistically diverse and highly regulated pathways macropinocytosis clathrin-mediated endocytosis caveolae-mediated endocyto-sis and Pincher-mediated endocytosis. The kinase activity of Trk is probably required for receptor internalization. 

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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. 

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... 

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... 

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. 

Neurotrophins can prime neurons for regeneration. They elevate cAMP in neurons in the absence of inhibitory signals, and this elevation sufficiently over-rides any subsequent inhibitory signals. In vivo, crushed DRG axons have been shown to regenerate into spinal cord by apphcation of neurotrophins (Ramer et al., 2000). Interestingly, effects of neurotrophins, in most cases, occur through Trk receptor, while inhibitory Summary effects are mediated through pVS. ... 

The substrates for neurotrophin Trk receptors-phos-pholipase C-y, PI3-K SHC and Grb2 adaptor proteins-are utilized by many tyrosine kinase receptors. This raises the question of how these phosphorylation events lead to different biological outcomes (Chao, 1992b). There are several possibilities. First, the strength and duration of the receptor autophosphorylation events may determine downstream signalling outcomes. Second, differential signalling may be controlled by specific dephosphorylation events. Third, there may be unique second messengers or substrates which determine the specific nature of the response. 

There are several ways to account for an association between receptors. For the Trk receptors, SH2-containing proteins serve as adaptor molecules that link to enzymatic functions. For p75 receptors, signalling intermediates used by TNF and Fas receptors, such as FADD and TRADD proteins, downstream effectors, such as caspase-8 and the FLICE/MACH interacting enzyme (Cleveland and Ihle, 1995) may be functional. It remains to be seen whether p75 utilize these adaptor proteins, or other interacting proteins of different specificity. 

Although the function of p75 ° remains unclear there are several putative roles for this receptor. It may facilitate signalling through the Trk receptors (Barker and Shooter, 1994 Verdi et al.,... 

In summary, neurotrophin signal transduction has been shown to be dependent on the presence of the appropriate trk receptors on the responsive cells. In contrast, p75 ° was found not to be necessary for neurotrophin signal transduction in vitro (Cordon-Cardo et al., 1991 Glass et al., 1991 Weskamp and Reichardt, 1991 Ibanez et al., 1992 Ip et al., 1993b). Its involvement as mediator of neurotrophin function in vivo is poorly understood, at the moment. However, it has been sug-... 

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