title: NGF and ProNGF: Regulation of neuronal and neoplastic responses through receptor signaling.
abstract: 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.
authors.affiliation: Dept of Pharmaceutical Chemistry, UCSF, San Francisco, CA, USA. Electronic address: rab@cgl.ucsf.edu.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Bradshaw
authors.affiliation: School of Biomedical Sciences & Pharmacy, Hunter Medical Research Institute, Faculty of Health and Medicine, University of Newcastle, Australia. Electronic address: jay.pundavela@newcastle.edu.au.
authors.forename: Jay
authors.initials: J
authors.lastname: Pundavela
authors.affiliation: Dept of Pharmaceutical Chemistry, UCSF, San Francisco, CA, USA. Electronic address: jordane.biarc@univ-lyon1.fr.
authors.forename: Jordane
authors.initials: J
authors.lastname: Biarc
authors.affiliation: Dept of Pharmaceutical Chemistry, UCSF, San Francisco, CA, USA. Electronic address: chalkley@cgl.ucsf.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Chalkley
authors.affiliation: Dept of Pharmaceutical Chemistry, UCSF, San Francisco, CA, USA. Electronic address: alb@cgl.ucsf.edu.
authors.forename: A L
authors.initials: AL
authors.lastname: Burlingame
authors.affiliation: School of Biomedical Sciences & Pharmacy, Hunter Medical Research Institute, Faculty of Health and Medicine, University of Newcastle, Australia. Electronic address: hubert.hondermarck@newcastle.edu.au.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hondermarck
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020932:Nerve Growth Factor / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016716:PC12 Cells; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D020917:Receptor, trkA / Q000235:genetics* / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D020932:Nerve Growth Factor; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor; D000099183:Sortilin; C502240:NGF protein, human; C484065:NGFR protein, human; C061397:pro-nerve growth factor, human
keywords: NGF; growth factor; phosphorylation; receptor tyrosine kinase; signaling