Nerve growth factor (NGF) is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons. It is perhaps the prototypical growth factor, in that it was one of the first to be described.

Since it was first isolated by Nobel Laureates Rita Levi-Montalcini and Stanley Cohen in 1956, numerous biological processes involving NGF have been identified, two of them being the survival of pancreatic beta cells and the regulation of the immune system.

NGF is initially in a 7S, 130-kDa complex of 3 proteins - Alpha-NGF, Beta-NGF, and Gamma-NGF (2:1:2 ratio) when expressed. This form of NGF is also referred to as proNGF (NGF precursor). The gamma subunit of this complex acts as a serine protease, and cleaves the N-terminal of the beta subunit, thereby activating the protein into functional NGF.

The term nerve growth factor usually refers to the 2.5S, 26-kDa beta subunit of the protein, the only component of the 7S NGF complex that is biologically active (i.e. acting as signaling molecules).

Function Of Nerve Growth Factor

As its name suggests, NGF is involved primarily in the growth, as well as the maintenance, proliferation, and survival of nerve cells (neurons). In fact, nerve growth factor is critical for the survival and maintenance of sympathetic and sensory neurons, as they undergo apoptosis in its absence. However, several recent studies suggest that NGF is also involved in pathways besides those regulating the life cycle of neurons.

NGF can drive the expression of genes such as bcl-2 by binding to the TrkA receptor, which stimulates the proliferation and survival of the target neuron.

Neuronal Proliferation

High affinity binding between proNGF, sortilin, and p75NTR can result in either survival or programmed cell death. Study results indicate that superior cervical ganglia neurons that express both p75NTR and TrkA die when treated with proNGF, while NGF treatment of these same neurons results in survival and axonal growth.

Survival and PCD mechanisms are mediated through adaptor protein binding to the death domain of the p75NTR cytoplasmic tail. Survival occurs when recruited cytoplasmic adaptor proteins facilitate signal transduction through tumor necrosis factor receptor members such as TRAF6, which results in the release of nuclear factor κB (NF-κB) transcription activator.[1] NF-κB regulates nuclear gene transcription to promote cell survival.

Alternatively, programmed cell death occurs when TRAF6 and neurotrophin receptor interacting factor (NRIF) are both recruited to activate c-Jun N-terminal kinase (JNK); which phosphorylates c-Jun. The activated transcription factor c-Jun regulates nuclear transcription via AP-1 to increase pro-apoptotic gene transcription.[1]

Ovulation

NGF is abundant in seminal plasma. Recent studies have found that it induces ovulation in some mammals e.g. “induced” ovulators, such as llamas.

Surprisingly, research showed that these induced animals will also ovulate when semen from on-schedule or “spontaneous” ovulators, such as cattle is used. Its significance in humans is unknown. It was previously dubbed ovulation-inducing factor (OIF) in semen before it was identified as beta-NGF in 2012.

Immune System Regulation

Nerve growth factor plays a critical role in the regulation of both innate and acquired immunity. In the process of inflammation, NGF is released in high concentrations by mast cells, and induces axonal outgrowth in nearby nociceptive neurons.

This leads to increased pain perception in areas under inflammation. In acquired immunity, NGF is produced by the Thymus as well as CD4+ T cell clones, inducing a cascade of maturation of T cells under infection.

Romantic Love

Recent studies found that the concentration of NGF in the blood plasma is significantly higher in individuals who have been in a romantic relationship with another person for less than 12 months [227 (14) pg/ml], than those who are either not in a romantic relationship [149 (12) pg/ml] or have been in one for more than 12 months [123 (10) pg/ml].

Nerve growth factor can indirectly stimulate the expression of adrenocorticotrophic hormone (ACTH) in the hypothalamic-pituitary-adrenal axis (HPA) by increasing vasopressin secretion. ACTH binds to the MC2 receptor in the zona fasciculata of the adrenal cortex, and stimulates secretion of the stress hormone cortisol.

This rapid increase of cortisol in the blood plasma can induce feelings of euphoria, which may explain the initial “rush” of falling in love. Studies show that ACTH can in turn stimulate NGF secretion in both the cerebral cortex and the hypothalamus.

Mechanism Of Action

Nerve growth factor binds with at least two classes of receptors: the tropomyosin receptor kinase A (TrkA) and low-affinity NGF receptor (LNGFR/p75NTR). Both are associated with neurodegenerative disorders.

When NGF binds to the TrkA receptor, it drives the homodimerization of the receptor, which in turn causes the autophosphorylation of the tyrosine kinase segment. This leads to the activation of PI 3-kinase, ras, and PLC signaling pathways. Alternatively, the p75NTR receptor can form a heterodimer with TrkA, which has higher affinity and specificity for NGF.

Studies suggest that NGF circulates throughout the entire body via the blood plasma, and is important for the overall maintenance of homeostasis.

Neuron Survival

Binding interaction between NGF and the TrkA receptor facilitates receptor dimerization and tyrosine residue phosphorylation of the cytoplasmic tail by adjacent Trk receptors. Trk receptor phosphorylation sites operate as Shc adaptor protein docking sites, which undergo phosphorylation by the TrkA receptor.

Once the cytoplasmic adaptor protein (Shc) is phosphorylated by the receptor cytoplasmic tail, cell survival is initiated through several intracellular pathways.

One major pathway leads to the activation of the serine/threonine kinase, Akt. This pathway begins with the Trk receptor complex-recruitment of a second adaptor protein called growth factor-receptor bound protein-2 (Grb2) along with a docking protein called Grb2-associated Binder-1 (GAB1).

Subsequently, phosphatidylinositol-3 kinase (PI3K) is activated, resulting in Akt kinase activation. Study results have shown that blocking PI3K or Akt activity results in death of sympathetic neurons in culture, regardless of NGF presence.  However, if either kinase is constitutively active, neurons survive even without NGF.

A second pathway contributing to cell survival occurs through activation of the mitogen-activated protein kinase (MAPK) kinase. In this pathway, recruitment of a guanine nucleotide exchange factor by the adaptor and docking proteins leads to activation of a membrane-associated G-protein known as Ras.

The guanine nucleotide exchange factor mediates Ras activation through the GDP-GTP exchange process. The active Ras protein phosphorylates several proteins, along with the serine/threonine kinase, Raf. Raf in turn activates the MAPK cascade to facilitate ribosomal s6 kinase (RSK) activation and transcriptional regulation.

Both Akt and RSK, components of the PI3K-Akt and MAPK pathways respectively, act to phosphorylate the cyclic AMP response element binding protein (CREB) transcription factor. Phosphorylated CREB translocates into the nucleus and mediates increased expression of anti-apoptotic proteins, thus promoting NGF-mediated cell survival.

However, in the absence of NGF, the expression of pro-apoptotic proteins is increased when the activation of cell death-promoting transcription factors such as c-Jun are not suppressed by the aforementioned NGF-mediated cell survival pathways.

[1] Sanes DH, Thomas AR, Harris WA (2011). “Naturally-occurring neuron death”. Development of the Nervous System, Third Edition. Boston: Academic Press. pp. 171–208. ISBN 978-0-12-374539-2.


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