Neurotrophic Factors
Martin Berry, Ann Logan in CNS Injuries: Cellular Responses and Pharmacological Strategies, 2019
The low-affinity p75 NGF receptor (p75NGFR)21–24 is a product of a different gene family and is a member of the tumor necrosis factor receptor superfamily. In contrast to the above-mentioned Trk receptor specificities, p75NGFR can bind all the neurotrophins. The p75NGFR provides ligand-binding specificity for NGF to TrkA, can enhance Trk phosphorylation in the presence of ligand, but can decrease TrkA autophosphorylation in the absence of NGF. In the peripheral nervous system p75NGFR facilitates retrograde transport of selected neurotrophins.26 The p75NGFR also has TrkA-independent signaling abilities through activation of sphingomyelin hydrolysis, which produces the lipid second messenger ceramide.27,28 Ceramide can induce apoptosis29,30 and recent in vitro and in vivo findings have revealed that p75NGFR can mediate neuronal apoptosis.31–33 Interestingly, activation of p75NGFR by all neurotrophins can produce ceramide, but in Schwann cells (which lack Trks), NGF, but not BDNF or NT-3, also causes activation of the transcription factor NFkB.34 This suggests that different ligands can activate different intracellular pathways through p75NGFR. The selective activation by different ligands of different signaling pathways that may result in cell death or survival through the same receptor may constitute a powerful therapeutic strategy.
Physiology of pain
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal in Principles of Physiology for the Anaesthetist, 2015
Nociceptors do not act simply as inert conductors of sensory information. Section of, or damage to, a peripheral nerve results in a number of biochemical, physiological and morphological changes. Damage to peripheral nerves will result in ectopic discharges near the site of damage and adjacent to the DRG (Figure 13.9). Nerve damage also results in an increased production of peptides, such as nerve growth factor (NGF), which normally regulate neuronal growth. NGF is a neurotropic peptide that activates the tyrosine kinase (Trk) receptor. Inflammation is associated with increased NGF expression and synthesis in peripheral tissues. NGF is important for the development of peripheral sensitization mediated by direct and indirect actions of inflammatory mediators on nociceptive afferents, mast cells and postganglionic efferents. Axonal transport of NGF has tropic effects within the spinal cord dorsal horn, resulting in central sensitization.
Thyroid
Pat Price, Karol Sikora in Treatment of Cancer, 2014
Although thyroid follicular cells can give rise to both benign and malignant tumours, the evidence to support an adenoma to carcinoma multi-step pathogenesis is not universally accepted. Malignant transformation is due to the activation of proto-oncogenes or the inactivation of tumour suppressor genes in combination with environmental factors. Defects to the tyrosine kinase (trk) receptor genes are commonly found in thyroid cancer. The interaction of these receptors with growth factors leads to the activation of the mitogen-activated protein kinase (MAPK) pathway through RAS and BRAF proteins, resulting in uncontrolled cell division. Abnormalities of the trk receptor genes have almost exclusively been associated with papillary carcinoma; these include ret/papillary thyroid cancer (PTC) rearrangements, trk rearrangements and met over-expression. The higher frequency of ret/PTC rearrangements in patients exposed to radiation following the Chernobyl accident suggests that radiation exposure may be one of the mechanisms leading to their activation.
Current status of biomarker testing in historically rare, high-unmet-need tumors: soft tissue sarcomas and thyroid cancers
Published in Expert Review of Anticancer Therapy, 2019
Bridgette Schroader, Sheldon Kong, Sibyl Anderson, Todd Williamson, Anthony Sireci, Kasia Shields
However, the first drug developed exclusively as a tumor-agnostic therapy was larotrectinib, a small molecule inhibitor targeting neurotrophic receptor tyrosine kinase (NTRK) gene fusions [22]. The NTRK gene encodes a tropomyosin receptor kinase (TRK) implicated in many routine body functions [23,24]. The TRK receptor family is composed of three transmembrane proteins, TRKA, TRKB, and TRKC; these transmembrane proteins are encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively [25]. TRKA, TRKB, and TRKC are expressed in human neuronal tissue and hold an essential role in the development and function of the nervous system through the activation of neurotrophins [25]. The binding of the neurotrophin to the TRK receptor results in the activation of signal transduction pathways leading to proliferation, differentiation, and survival in normal cells [25].
Larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor for the treatment of TRK fusion cancer
Published in Expert Review of Clinical Pharmacology, 2019
Tropomyosin receptor kinase (TRK) proteins are a tyrosine receptor kinase family composed of three members, TRKA, TRKB, and TRKC, that are widely expressed in the nervous system and in many non-neuronal tissue types [1]. TRKA, B, and C are encoded by the neurotrophic tyrosine receptor kinase (NTRK) genes, NTRK1, NRTK2, and NTRK3, respectively [1]. During neuronal development, the TRK proteins mediate neuronal survival and synaptic plasticity in both the central and peripheral nervous systems [2]. TRK receptors are physiologically activated by interactions with their primary neurotrophin ligands, which bind to the extracellular domain of the receptor. Specificity of neurotrophin ligand binding is TRK receptor type dependent and subsequent interactions induce receptor homodimerization, phosphorylation of tyrosine residues on the cytoplasmic domains, and activation of downstream signaling pathways known to be associated with growth and development (Figure 1). TRKA mediates signaling via the MAPK and RAS/ERK pathways, which promote proliferation and differentiation of neurons, TRKB activates the RAS/ERK and PI3K signaling pathways, essential for the survival of neurons, and TRKC activates the PI3K/AKT pathway, thereby preventing apoptosis and increasing cell survival [1].
Transcriptomic and functional proteomics analyses to unveil the common and unique pathway(s) of neuritogenesis induced by Russell’s viper venom nerve growth factor in rat pheochromocytoma neuronal cells
Published in Expert Review of Proteomics, 2021
Taufikul Islam, Dev Madhubala, Rupak Mukhopadhyay, Ashis K. Mukherjee
Nerve growth factor (NGF), an orthologous variant of one of the classes of neurotrophins in animal systems, is one of the minor components of SV [2,3]. The molecular mass of SV NGF has been determined to be in the range of 12–37 KDa [4–7], which is much smaller than those of mammalian NGFs [8]. To exert their biological activity (neuritogenesis), mammalian neurotrophins (conventional NGFs) can bind with variable affinities to two separate classes of cellular receptors: (i) high-affinity binding (Kd ~10−10 to 10−11 M) to tropomyosin-related kinase (Trk) receptor, a specific class of receptor tyrosine kinases [9], and (ii) low-affinity binding (Kd ~10−9 M) to a member of the tumor necrosis factor (TNF) receptor superfamily p75 neurotrophin receptor of the p75NTR class of receptor [10]. Post binding to these receptors, mammalian neurotrophins activate a complex array of intracellular cascades including Trk-initiated, Ras-mediated activation of MAPK or PI3K pathway, and activation of the PLC-γ pathway [11]; or the p75NT receptor-mediated survivability factor to induce neuritogenesis [12]. Mammalian neurotrophins thus play an important role in nerve growth, regeneration, and survival.
Related Knowledge Centers
- Biochemical Cascade
- Chemical Synapse
- Growth Factor
- Ligand
- Nervous System
- Neurotrophin
- Receptor Tyrosine Kinase
- Synaptic Plasticity
- Cellular Differentiation
- Neuron