Abstract
Growth factors such as the neurotrophins promote neuronal survival and shape neuronal morphology. Neurotrophin receptors are located on the surface of axons and dendrites and must convey their signal retrogradely to the nucleus to influence transcription of target genes. The distance between the site of receptor activation and the nucleus is tremendous. How is the retrograde transmission of survival signals being achieved? Recent work showed that signaling endosomes containing neurotrophin receptors and associated downstream kinases undergo retrograde vesicular transport along microtubules, propelled by the molecular motor dynein. The next objective in the “neurotrophin receptor trafficking meets signal transduction field” will be to elucidate the traffic control mechanisms governing the directed movement of signaling endosomes. Much is already known on the trafficking of the receptor for epidermal growth factor, EGFR. We will summarize the known traffic control mechanisms for EGFR and hypothesize whether EGFR-relevant traffic control mechanisms might also be relevant for neurotrophin receptor traffic control. Moreover, we speculate about potential implications of neurotrophin receptor traffic jams for neurodegenerative diseases.
Similar content being viewed by others
References
Snider WD (1994) Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77:627–638
Bothwell M (1995) Functional interactions of neurotrophins and neurotrophin receptors. Annu Rev Neurosci 18:223–253
Segal RA, Greenberg ME (1996) Intracellular signaling pathways activated by neurotrophic factors. Annu Rev Neurosci 19:463–489
Hendry IA, Stockel K, Thoenen H, Iversen LL (1974) The retrograde axonal transport of nerve growth factor. Brain Res 68:103–121
Ehlers MD, Kaplan DR, Price DL, Koliatsos VE (1995) NGF-stimulated retrograde transport of trkA in the mammalian nervous system. J Cell Biol 130:149–156
Grimes ML, Zhou J, Beattie EC, Yuen EC, Hall DE, Valletta JS, Topp KS, LaVail JH, Bunnett NW, Mobley WC (1996) Endocytosis of activated TrkA: evidence that nerve growth factor induces formation of signaling endosomes. J Neurosci 16:7950–7964
Heerssen HM, Pazyra MF, Segal RA (2004) Dynein motors transport activated Trks to promote survival of target-dependent neurons. Nat Neurosci 7:596–604
Howe CL, Mobley WC (2004) Signaling endosome hypothesis: a cellular mechanism for long distance communication. J Neurobiol 58:207–216
Zweifel LS, Kuruvilla R, Ginty DD (2005) Functions and mechanisms of retrograde neurotrophin signalling. Nat Rev Neurosci 6:615–625
Heerssen HM, Segal RA (2002) Location, location, location: a spatial view of neurotrophin signal transduction. Trends Neurosci 25:160–165
MacInnis BL, Campenot RB (2002) Retrograde support of neuronal survival without retrograde transport of nerve growth factor. Science 295:1536–1539
Senger DL, Campenot RB (1997) Rapid retrograde tyrosine phosphorylation of trkA and other proteins in rat sympathetic neurons in compartmented cultures. J Cell Biol 138:411–421
Deisseroth K, Bito H, Tsien RW (1996) Signaling from synapse to nucleus: postsynaptic CREB phosphorylation during multiple forms of hippocampal synaptic plasticity. Neuron 16:89–101
Berridge MJ (1993) Cell signalling. A tale of two messengers. Nature 365:388–389
Miyashiro K, Dichter M, Eberwine J (1994) On the nature and differential distribution of mRNAs in hippocampal neurites: implications for neuronal functioning. Proc Natl Acad Sci U S A 91:10800–10804
Hanz S, Perlson E, Willis D, Zheng JQ, Massarwa R, Huerta JJ, Koltzenburg M, Kohler M, van-Minnen J, Twiss JL (2003) Axoplasmic importins enable retrograde injury signaling in lesioned nerve. Neuron 40:1095–1104
Thompson KR, Otis KO, Chen DY, Zhao Y, O’Dell TJ, Martin KC (2004) Synapse to nucleus signaling during long-term synaptic plasticity; a role for the classical active nuclear import pathway. Neuron 44:997–1009
Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D (2003) NF-kappa B functions in synaptic signaling and behavior. Nat Neurosci 6:1072–1078
Graef IA, Wang F, Charron F, Chen L, Neilson J, Tessier-Lavigne M, Crabtree GR (2003) Neurotrophins and netrins require calcineurin/NFAT signaling to stimulate outgrowth of embryonic axons. Cell 113:657–670
Burke MA, Bothwell M (2003) p75 neurotrophin receptor mediates neurotrophin activation of NF-kappa B and induction of iNOS expression in P19 neurons. J Neurobiol 55:191–203
Groth RD, Mermelstein PG (2003) Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T-cells)-dependent transcription: a role for the transcription factor NFATc4 in neurotrophin-mediated gene expression. J Neurosci 23:8125–8134
Gruenberg J (2001) The endocytic pathway: a mosaic of domains. Nat Rev Mol Cell Biol 2:721–730
Lakadamyali M, Rust MJ, Zhuang X (2006) Ligands for clathrinmediated endocytosis are differentially sorted into distinct populations of early endosomes. Cell 124:997–1009
Ishiki M, Klip A (2005) Minireview: recent developments in the regulation of glucose transporter-4 traffic: new signals, locations, and partners. Endocrinology 146:5071–5078
Meier O, Boucke K, Hammer SV, Keller S, Stidwill RP, Hemmi S, Greber UF (2002) Adenovirus triggers macropinocytosis and endosomal leakage together with its clathrin-mediated uptake. J Cell Biol 158:1119–1131
Pelkmans L, Burli T, Zerial M, Helenius A (2004) Caveolin-stabilized membrane domains as multifunctional transport and sorting devices in endocytic membrane traffic. Cell 118:767–780
Felder S, Miller K, Moehren G, Ullrich A, Schlessinger J, Hopkins CR (1990) Kinase activity controls the sorting of the epidermal growth factor receptor within the multivesicular body. Cell 61:623–634
Petiot A, Faure J, Stenmark H, Gruenberg J (2003) PI3P signaling regulates receptor sorting but not transport in the endosomal pathway. J Cell Biol 162:971–979
Vieira AV, Lamaze C, Schmid SL (1996) Control of EGF receptor signaling by clathrin-mediated endocytosis. Science 274:2086–2089
Zerial M, McBride H (2001) Rab proteins as membrane organizers. Nat Rev Mol Cell Biol 2:107–117
Barbieri MA, Fernandez-Pol S, Hunker C, Horazdovsky BH, Stahl PD (2004) Role of rab5 in EGF receptor-mediated signal transduction. Eur J Cell Biol 83:305–314
Lanzetti L, Rybin V, Malabarba MG, Christoforidis S, Scita G, Zerial M, Di Fiore PP (2000) The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5. Nature 408:374–377
Ceresa BP, Bahr SJ (2006) Rab7 activity affects epidermal growth factor: epidermal growth factor receptor degradation by regulating endocytic trafficking from the late endosome. J Biol Chem 281:1099–1106
Dikic I (2003) Mechanisms controlling EGF receptor endocytosis and degradation. Biochem Soc Trans 31:1178–1181
Raiborg C, Bache KG, Gillooly DJ, Madshus IH, Stang E, Stenmark H (2002) Hrs sorts ubiquitinated proteins into clathrin-coated microdomains of early endosomes. Nat Cell Biol 4:394–398
Komada M, Kitamura N (1995) Growth factor-induced tyrosine phosphorylation of Hrs, a novel 115-kilodalton protein with a structurally conserved putative zinc finger domain. Mol Cell Biol 15:6213–6221
Bache KG, Raiborg C, Mehlum A, Madshus IH, Stenmark H (2002) Phosphorylation of Hrs downstream of the epidermal growth factor receptor. Eur J Biochem 269:3881–3887
Urbe S, Sachse M, Row PE, Preisinger C, Barr FA, Strous G, Klumperman J, Clague MJ (2003) The UIM domain of Hrs couples receptor sorting to vesicle formation. J Cell Sci 116:4169–4179
Katzmann DJ, Babst M, Emr SD (2001) Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I. Cell 106:145–155
Lu Q, Hope LW, Brasch M, Reinhard C, Cohen SN (2003) TSG101 interaction with HRS mediates endosomal trafficking and receptor downregulation. Proc Natl Acad Sci USA 100:7626–7631
Wagner KU, Krempler A, Qi Y, Park K, Henry MD, Triplett AA, Riedlinger G, Rucker IE, Hennighausen L (2003) Tsg101 is essential for cell growth, proliferation, and cell survival of embryonic and adult tissues. Mol Cell Biol 23:150–162
Di Fiore PP, De Camilli P (2001) Endocytosis and signaling: an inseparable partnership. Cell 106:1–4
Dinneen JL, Ceresa BP (2004) Continual expression of Rab5(Q79L) causes a ligand-independent EGFR internalization and diminishes EGFR activity. Traffic 5:606–615
Scoles DR, Qin Y, Nguyen V, Gutmann DH, Pulst SM (2005) HRS inhibits EGF receptor signaling in the RT4 rat schwannoma cell line. Biochem Biophys Res Commun 335:385–392
Polo S, Di Fiore PP (2006) Endocytosis conducts the cell signaling orchestra. Cell 124:897–900
Layer PG, Shooter EM (1983) Binding and degradation of nerve growth factor by PC12 pheochromocytoma cells. J Biol Chem 258:3012–3018
Saxena S, Howe CL, Cosgaya JM, Steiner P, Hirling H, Chan JR, Weis J, Kruttgen A (2005) Differential endocytic sorting of p75NTR and TrkA in response to NGF: a role for late endosomes in TrkA trafficking. Mol Cell Neurosci 28:571–587
Howe CL, Valletta JS, Rusnak AS, Mobley WC (2001) NGF signaling from clathrin-coated vesicles: evidence that signaling endosomes serve as a platform for the Ras-MAPK pathway. Neuron 32:801–814
Saxena S, Howe CL, Cosgaya JM, Hu M, Weis J, Kruttgen A (2004) Differences in the surface binding and endocytosis of neurotrophins by p75NTR. Mol Cell Neurosci 26:292–307
Delcroix JD, Valletta JS, Wu C, Hunt SJ, Kowal AS, Mobley WC (2003) NGF signaling in sensory neurons: evidence that early endosomes carry NGF retrograde signals. Neuron 39:69–84
Valdez G, Akmentin W, Philippidou P, Kuruvilla R, Ginty DD, Halegoua S (2005) Pincher-mediated macroendocytosis underlies retrograde signaling by neurotrophin receptors. J Neurosci 25:5236–5247
Saxena S, Bucci C, Weis J, Kruttgen A (2005) The small GTPase Rab7 controls the endosomal trafficking and neuritogenic signaling of the nerve growth factor receptor TrkA. J Neurosci 25:10930–10940
Parton RG, Simons K, Dotti CG (1992) Axonal and dendritic endocytic pathways in cultured neurons. J Cell Biol 119:123–137
Claude P, Hawrot E, Dunis DA, Campenot RB (1982) Binding, internalization, and retrograde transport of 125I-nerve growth factor in cultured rat sympathetic neurons. J Neurosci 2:431–442
Ure DR, Campenot RB (1997) Retrograde transport and steady-state distribution of 125I-nerve growth factor in rat sympathetic neurons in compartmented cultures. J Neurosci 17:1282–1290
Sorkin A, Von Zastrow M (2002) Signal transduction and endocytosis: close encounters of many kinds. Nat Rev Mol Cell Biol 3:600–614
Bhattacharyya A, Watson FL, Pomeroy SL, Zhang YZ, Stiles CD, Segal RA (2002) High-resolution imaging demonstrates dynein-based vesicular transport of activated Trk receptors. J Neurobiol 51:302–312
Wunderlich W, Fialka I, Teis D, Alpi A, Pfeifer A, Parton RG, Lottspeich F, Huber LA (2001) A novel 14-kilodalton protein interacts with the mitogen-activated protein kinase scaffold mp1 on a late endosomal/lysosomal compartment. J Cell Biol 152:765–776
Oksvold MP, Skarpen E, Wierod L, Paulsen RE, Huitfeldt HS (2001) Re-localization of activated EGF receptor and its signal transducers to multivesicular compartments downstream of early endosomes in response to EGF. Eur J Cell Biol 80:285–294
Bilderback TR, Gazula VR, Lisanti MP, Dobrowsky RT (1999) Caveolin interacts with Trk A and p75(NTR) and regulates neurotrophin signaling pathways. J Biol Chem 274:257–263
Huang CS, Zhou J, Feng AK, Lynch CC, Klumperman J, DeArmond SJ, Mobley WC (1999) Nerve growth factor signaling in caveolae-like domains at the plasma membrane. J Biol Chem 274:36707–36714
Peiro S, Comella JX, Enrich C, Martin-Zanca D, Rocamora N (2000) PC12 cells have caveolae that contain TrkA. Caveolae-disrupting drugs inhibit nerve growth factor-induced, but not epidermal growth factor-induced, MAPK phosphorylation. J Biol Chem 275:37846–37852
Sigismund S, Woelk T, Puri C, Maspero E, Tacchetti C, Transidico P, Di Fiore PP, Polo S (2005) Clathrin-independent endocytosis of ubiquitinated cargos. Proc Natl Acad Sci USA 102:2760–2765
Tsui-Pierchala BA, Ginty DD (1999) Characterization of an NGF-P-TrkA retrograde-signaling complex and age-dependent regulation of TrkA phosphorylation in sympathetic neurons. J Neurosci 19:8207–8218
Bronfman FC, Tcherpakov M, Jovin TM, Fainzilber M (2003) Ligand-induced internalization of the p75 neurotrophin receptor: a slow route to the signaling endosome. J Neurosci 23:3209–3220
Barker PA, Shooter EM (1994) Disruption of NGF binding to the low affinity neurotrophin receptor p75LNTR reduces NGF binding to TrkA on PC12 cells. Neuron 13:203–215
Dombrowski L, Faure R, Marette A (2000) Sustained activation of insulin receptors internalized in GLUT4 vesicles of insulin-stimulated skeletal muscle. Diabetes 49:1772–1782
Chen ZY, Ieraci A, Tanowitz M, Lee FS (2005) A novel endocytic recycling signal distinguishes biological responses of Trk neurotrophin receptors. Mol Biol Cell 16:5761–5772
Zapf-Colby A, Olefsky JM (1998) Nerve growth factor processing and trafficking events following TrkA-mediated endocytosis. Endocrinology 139:3232–3240
Hendriks BS, Opresko LK, Wiley HS, Lauffenburger D (2003) Quantitative analysis of HER2-mediated effects on HER2 and epidermal growth factor receptor endocytosis: distribution of homo- and heterodimers depends on relative HER2 levels. J Biol Chem 278:23343–23351
Hendriks BS, Wiley HS, Lauffenburger D (2003) HER2-mediated effects on EGFR endosomal sorting: analysis of biophysical mechanisms. Biophys J 85:2732–2745
Lad SP, Peterson DA, Bradshaw RA, Neet KE (2003) Individual and combined effects of TrkA and p75NTR nerve growth factor receptors. A role for the high affinity receptor site. J Biol Chem 278:24808–24817
Zhang Y, Moheban DB, Conway BR, Bhattacharyya A, Segal RA (2000) Cell surface Trk receptors mediate NGF-induced survival while internalized receptors regulate NGF-induced differentiation. J Neurosci 20:5671–5678
Makkerh JP, Ceni C, Auld DS, Vaillancourt F, Dorval G, Barker PA (2005) p75 neurotrophin receptor reduces ligand-induced Trk receptor ubiquitination and delays Trk receptor internalization and degradation. EMBO Rep 6:936–941
Geetha T, Jiang J, Wooten MW (2005) Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling. Mol Cell 20:301–312
Arevalo JC, Waite J, Rajagopal R, Beyna M, Chen ZY, Lee FS, Chao MV (2006) Cell survival through Trk neurotrophin receptors is differentially regulated by ubiquitination. Neuron 50:549–559
Bibel M, Hoppe E, Barde YA (1999) Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR. Embo J 18:616–622
Ohrt T, Mancini A, Tamura T, Niedenthal R (2004) c-Cbl binds to tyrosine-phosphorylated neurotrophin receptor p75 and induces its ubiquitination. Cell Signal 16:1291–1298
Scott PM, Bilodeau PS, Zhdankina O, Winistorfer SC, Hauglund MJ, Allaman MM, Kearney WR, Robertson AD, Boman AL, Piper RC (2004) GGA proteins bind ubiquitin to facilitate sorting at the trans-Golgi network. Nat Cell Biol 6:252–259
Appel SH (1981) A unifying hypothesis for the cause of amyotrophic lateral sclerosis, parkinsonism, and Alzheimer disease. Ann Neurol 10:499–505
Kruttgen A, Saxena S, Evangelopoulos ME, Weis J (2003) Neurotrophins and neurodegenerative diseases: receptors stuck in traffic? J Neuropathol Exp Neurol 62:340–350
Cooper JD, Salehi A, Delcroix JD, Howe CL, Belichenko PV, Chua-Couzens J, Kilbridge JF, Carlson EJ, Epstein CJ, Mobley WC (2001) Failed retrograde transport of NGF in a mouse model of Down’s syndrome: reversal of cholinergic neurodegenerative phenotypes following NGF infusion. Proc Natl Acad Sci USA 98:10439–10444
Hefti F (1986) Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections. J Neurosci 6:2155–2162
Chen KS, Nishimura MC, Armanini MP, Crowley C, Spencer SD, Phillips HS (1997) Disruption of a single allele of the nerve growth factor gene results in atrophy of basal forebrain cholinergic neurons and memory deficits. J Neurosci 17:7288–7296
Capsoni S, Ugolini G, Comparini A, Ruberti F, Berardi N, Cattaneo A (2000) Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice. Proc Natl Acad Sci USA 97:6826–6831
Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, Patel P, Blesch A, Vahlsing HL, Ho G (2005) A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 11:551–555
Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307:1282–1288
Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K, Chung PP (2006) Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 51:29–42
Kamal A, Almenar-Queralt A, LeBlanc JF, Roberts EA, Goldstein LS (2001) Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature 414:643–648
Lazarov O, Morfini GA, Lee EB, Farah MH, Szodorai A, DeBoer SR, Koliatsos VE, Kins S, Lee VM, Wong PC (2005) Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus: revisited. J Neurosci 25:2386–2395
Gauthier LR, Charrin BC, Borrell-Pages M, Dompierre JP, Rangone H, Cordelieres FP, De Mey J, MacDonald ME, Lessmann V, Humbert S (2004) Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118:127–138
Acknowledgement
We would like to thank Dr. Dana Dodd for critical reading of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Moises, T., Dreier, A., Flohr, S. et al. Tracking TrkA’s Trafficking: NGF Receptor Trafficking Controls NGF Receptor Signaling. Mol Neurobiol 35, 151–159 (2007). https://doi.org/10.1007/s12035-007-8000-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-007-8000-1