Bradshaw Ralph A, Pundavela Jay, Biarc Jordane, Chalkley Robert J, Burlingame A L, Hondermarck Hubert
Dept of Pharmaceutical Chemistry, UCSF, San Francisco, CA, USA.
School of Biomedical Sciences & Pharmacy, Hunter Medical Research Institute, Faculty of Health and Medicine, University of Newcastle, Australia.
Adv Biol Regul. 2015 May;58:16-27. doi: 10.1016/j.jbior.2014.11.003. Epub 2014 Nov 20.
Nerve growth factor (NGF) and its precursor (proNGF) are primarily considered as regulators of neuronal function that induce their responses via the tyrosine kinase receptor TrkA and the pan-neurotrophin receptor p75NTR. It has been generally held that NGF exerts its effects primarily through TrkA, inducing a cascade of tyrosine kinase-initiated responses, while proNGF binds more strongly to p75NTR. When this latter entity interacts with a third receptor, sortilin, apoptotic responses are induced in contrast to the survival/differentiation associated with the other two. Recent studies have outlined portions of the downstream phosphoproteome of TrkA in the neuronal PC12 cells and have clarified the contribution of individual docking sites in the TrkA endodomain. The patterns observed showed a similarity with the profile induced by the epidermal growth factor receptor, which is extensively associated with oncogenesis. Indeed, as with other neurotrophic factors, the distribution of TrkA and p75NTR is not limited to neuronal tissue, thus providing an array of targets outside the nervous systems. One such source is breast cancer cells, in which NGF and proNGF stimulate breast cancer cell survival/growth and enhance cell invasion, respectively. This latter activity is exerted via TrkA (as opposed to p75NTR) in conjunction with sortilin. Another tissue overexpressing proNGF is prostate cancer and here the ability of cancer cells to induce neuritogenesis has been implicated in cancer progression. These studies show that the non-neuronal functions of proNGF/NGF are likely integrated with their neuronal activities and point to the clinical utility of these growth factors and their receptors as biomarkers and therapeutic targets for metastasis and cancer pain.
神经生长因子（NGF）及其前体（proNGF）主要被视为神经元功能的调节因子，它们通过酪氨酸激酶受体TrkA和泛神经营养因子受体p75NTR诱导相应反应。一般认为，NGF主要通过TrkA发挥作用，引发一系列酪氨酸激酶启动的反应，而proNGF与p75NTR的结合更强。当后者与第三种受体sortilin相互作用时，会诱导凋亡反应，这与另外两种受体相关的存活/分化作用相反。最近的研究概述了神经元PC12细胞中TrkA下游磷酸化蛋白质组的部分情况，并阐明了TrkA胞内结构域中各个对接位点的作用。观察到的模式与表皮生长因子受体诱导的模式相似，后者与肿瘤发生广泛相关。事实上，与其他神经营养因子一样，TrkA和p75NTR的分布并不局限于神经组织，从而在神经系统之外提供了一系列靶点。其中一个来源是乳腺癌细胞，在这些细胞中，NGF和proNGF分别刺激乳腺癌细胞的存活/生长并增强细胞侵袭能力。后一种活性是通过TrkA（而非p75NTR）与sortilin共同发挥作用的。另一个过表达proNGF的组织是前列腺癌，癌细胞诱导神经突生长的能力与癌症进展有关。这些研究表明，proNGF/NGF的非神经元功能可能与其神经元活性整合在一起，并指出这些生长因子及其受体作为转移和癌痛的生物标志物和治疗靶点具有临床应用价值。
