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Nerve Growth Factor Signaling Pathway

Figure1. Nerve growth factor signaling pathway

An overview of nerve growth factor

Nerve growth factor (NGF) is one of the most important biologically active molecules in the nervous system. It plays an important role and has clinical significance in regulating the growth, development, differentiation, survival of nerve cells and the regeneration and repair of injured nerves. Current basic research indicates that NGF can be applied to neurotoxicity, peripheral nerve injury, diabetic peripheral neuropathy, senile dementia, Parkinson's disease, facial neuritis, and nerve damage (including spinal cord injury, high paraplegia, finger replantation, and neurological diseases). Brain damage and other peripheral nervous system damages are the only neurological protein factors currently available for clinical use. NGF has been in the historical process of early discovery to medical applications for more than half a century. Human nerve growth factor (hNGF) is a biologically active factor found in the human body that has a trophic effect on normal nerve cells and regulates the function of damaged nerve repair. It can maintain the survival of sympathetic and sensory nerves and promote nerve cells. The differentiation determines the direction of axon stretching and plays a decisive role in promoting brain development, nervous system growth, damage nerve regeneration and functional recovery.

Nerve growth factor family

NGF is synthesized as precursor in vivo, including signal peptides, leader peptides, and mature peptides. The signal peptide contributes to protein secretion. Two conserved regions in the leader peptide are required for NGF expression, enzymatic hydrolysis to form biologically active proteins, and secretion of mature NGF. It has now been found that leader peptides also contribute to the correct folding of proteins, and such leader peptides are known as molecular chaperones (IMCs). Therefore, it is considered that the leader peptide may play an intramolecular molecular chaperone role in the folding process of NGF. ProNGF contains a potential N-glycosylation site, and studies by Seidah et al. have shown that the propeptide portion of the NGF precursor can be N-glycosylated, and the glycosylation of proNGF helps to secrete the endoplasmic reticulum. ProNGF undergoes post-translational modifications at the N-terminus and C-terminus to form biologically active mature NGF. Furin and a small amount of prohormone convertase are capable of processing the N-terminus of the NGF precursor. The C-terminal modification occurs on a pair of Arg residues. In the submandibular gland of mice, the γ-NGF subunit complexed with β-NGF is capable of processing the N-terminal and C-terminal Arg residues of proNGF, promoting the formation of intermediates and mature NGF. In addition, the free NH2 terminus is required for NGF-binding receptors, and mutations at positions 112-115 of the NGFC-terminus can significantly affect the activity of NGF and can affect the stability of NGF structure. There are 6 cysteine residues in the mature NGF chain, which can form 3 pairs of intrachain disulfide bonds. The formation of disulfide bonds is a necessary condition for NGF to be activated. There are four neurotrophic factors in mammals, namely NGF, BDNF, NT-3 and NT-4 / 5, which act by binding to four receptors (p75NTR, TrkA, TrkB and TrkC). All four neurotrophic factors bind to the p75NTR receptor but selectively bind to the Trk receptor.

Nerve growth factor signaling pathway

  1. Nerve growth factor signaling pathway cascade
    Nerve growth factor has a wide range of biological effects, mainly through the following aspects: (1) nerve regeneration: directly in the regeneration of axons, through receptor-mediated intracellular signaling, activation of various differentiation factors, play a neurochemical function, guide and accelerate axon growth; regulate the proliferation and differentiation of Schwann cells. (2) Promote the germination of nerves. (3) Protection of damaged neurons: reduce the death of damaged nerve cells and regulate the gene expression of damaged neurons. (4) Promote inflammatory response chemotaxis and revascularization of recurrent nerves. NGF promotes the formation of new blood vessels. The mechanism is that NGF can promote the release of Ca2+ into the extracellular cells. The exothermic Ca2+ leads to increased tension of nerve cells, decreased excitability, and enhanced vasodilation, thereby increasing blood flow. It also promotes cell differentiation of muscle spindles after neuropathy and promotes the repair of fibroblasts in the skin and lungs. Studies have found that NGF is one of the important regulators of pancreatic cell physiology in adult rats, which can enhance the insulin secretion caused by glucose. This may be one of the mechanisms of autocrine or paracrine regulation. In addition, studies have found that osteogenic cells have low-affinity receptor NGF. Endogenous and exogenous NGF can bind to LNGFR and achieve intercellular signal transmission, thereby enhancing phosphorylating osteoblasts and osteogenesis. Studies have shown that NGF mRNA is significantly elevated in the brain after severe craniocerebral trauma, and its optimal receptor Trk-A mRNA is also expressed in non-injury sites, indicating that NGF responds to neurons in non-injured sites. Goss et al found that NGF increased in the cerebral cortex after brain trauma, and the activity of antioxidant enzymes also increased significantly. Therefore, it is believed that NGF can play a role by inducing the synthesis of oxygen radical scavengers. For the influence of central cholinergic on the nervous system, it is suggested that NGF can reduce the demyelinating degeneration and necrosis of cholinergic neurons, promote the release of acetylcholine from hippocampal neurons, and improve the memory disorder formed after brain injury. From the current research, the protective effect of NGF expression in the brain on brain damage may be classified into the following aspects: To improve the activity of free radical scavenger and increase the activity of catalase, superoxide dismutase, glutathione. The activity of free radical scavengers such as glycopeptide peroxidase reduces the damage of ischemic nerve cells; To antagonize the neurotoxicity of excitatory amino acids by regulating the cytoplasmic Ca2+ levels in neurons through various ways and means, thereby protecting the injured neurons and inhibiting programmed cell death. To increase cerebral blood flow and improve damage caused by cerebral ischemia. BDNF is present in the cerebral cortex, medulla, cerebellum, hippocampus, etc., and its receptor is Trk-B. BDNF mRNA is transiently increased after brain injury and has a faster response than NGF. BDNF has a trophic effect on motor neurons, inhibits motor neuron degeneration, and induces nerve growth. BDNF has a nutritional effect on cultured embryonic basal forebrain cholinergic neurons, midbrain dopaminergic neurons and aminobutyric acid neurons, and also protects mesenchymal dopaminergic neurons from the toxic effect of 2-phenylpyridine.
  2. Pathway regulation
    The expression of NGF is affected by a variety of biological factors, organic compounds and physical factors. It has been found that erythropoietin can enhance the expression of NGF gene. Song and other studies found that ethylenoate (EPA) can up-regulate the expression of NGF. Wang et al. showed that human cytomegalovirus can down-regulate endogenous NGF levels in human glioma cell line U251. Yoshipa et al found that edaravone and carnosic acid can induce the expression of human glial cells exposed to hypoxia/reoxygenation NGF. Studies have found that dexamethasone inhibits TGF-β1 induced NGF expression. Ha and other experimental studies have shown that injection of botulinum A into the bladder wall can up-regulate the expression of NGF. Wu Feng and other studies found that chronic stress of depression drugs can reduce the expression of NGF in hippocampus of rats, while antidepressants fluoxetine and tianeptine can reverse the decrease of NGF expression in hippocampus of chronic stress depression model rats. Many studies have shown that the expression of NGF is significantly different in the physiological and pathological state of the body. Zucchi et al. showed that the expression of NGF in the muscle layer around the urethra was significantly increased after excision of the rat ovary. When Barthel et al studied spine arthritis and rheumatoid arthritis patients, the expression of brain-derived neurotrophic factor and NGF mRNA was significantly increased. The expression of NGF and its receptor trkA is also affected to varying degrees in the traumatic state. Mao et al found that chronic unpredictable stress can lead to decreased expression of NGF in hippocampus of rats. In the study of rabbit mandibular model fracture healing test, Recent studies have confirmed that traditional Chinese medicine has a certain effect on the expression of NGF. Mao et al. showed that antidepressant Chinese medicine can reverse the decrease of NGF expression in hippocampus of chronic stress depression model rats. Cui and other studies have found that Angelica injection can increase brain-derived neurotrophic factor and nerve growth factor expression.
  3. Relationship with disease
    Alzheimer's disease
    Phase II clinical trials are underway for the treatment of Alzheimer's disease by injection of the AAV2 vector to express human NGF into the basal ganglia. Advantages of this gene therapy compared with traditional therapy are: (1) one-time intracerebral injection can reduce the risk of local inflammation and intracranial infection; (2) NGF penetrates the blood-brain barrier and directly exerts biological effects and reduces side effects. The secretion of NGF after injection can be long-term nutrition of neurons and continue to play a role. However, its shortcoming is that it is difficult to control the expression of NGF in the brain.
    Peripheral neuropathy
    When the peripheral nerve is destroyed, the expression level of NGF receptor is up-regulated within 6h. NGF can also slow down the growth retardation of neurons induced by chemotherapy drugs and can effectively prevent and control the sympathetic nerve damage caused by paclitaxel and vincristine. Use with cisplatin or with NGF first can improve cisplatin-induced peripheral neuropathy.
    Tumor
    In recent years, there have been more and more studies on the correlation between NGF and tumors. The expression of NGF and its receptors has been detected in various tumors such as breast cancer, pancreatic cancer and lung cancer, and participates in tumor proliferation and differentiation, apoptosis and angiogenesis. Compared with the normal pancreas, the mRNA levels of NGF and its receptor TrkA in pancreatic cancer tissues increased by 2.7-fold and 5.6-fold, respectively. High levels expression of NGF and its receptors significantly enhance the invasive ability of pancreatic cancer cells to peripheral nerves.

References

  1. Davidson B, Reich R, Lazarovici P, et al. Expression and activation of the nerve growth factor receptor TrkA in serous ovarian carcinoma. Clinical Cancer Research. 2003, 9(6):2248-2259.
  2. Kniewallner K M, Grimm N, Humpel C. Platelet-derived nerve growth factor supports the survival of cholinergic neurons in organotypic rat brain slices. Neuroscience Letters. 2014, 574:64-69.
  3. Bellini F, Toffano G, Bruni A. Activation of phosphoinositide hydrolysis by nerve growth factor and lysophosphatidylserine in rat peritoneal mast cells. Biochimica Et Biophysica Acta. 1988, 970(2):187-193.
  4. Galli A. Can the Nerve Growth Factor promote the reinnervation of the transplanted heart? Medical Hypotheses. 2014, 82(2):229-230.
  5. Stukel J, Thompson S, Simon L, et al. Polyethlyene glycol microgels to deliver bioactive nerve growth factor. Journal of Biomedical Materials Research Part A. 2015, 103(2):604-613.

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