Skip to main content
NCBI home page
The EMBO Journal logoLink to The EMBO Journal
. 1998 May 1;17(9):2534–2542. doi: 10.1093/emboj/17.9.2534

Early evolutionary origin of the neurotrophin receptor family.

R E van Kesteren 1, M Fainzilber 1, G Hauser 1, J van Minnen 1, E Vreugdenhil 1, A B Smit 1, C F Ibáñez 1, W P Geraerts 1, A G Bulloch 1
PMCID: PMC1170595  PMID: 9564036

Abstract

Neurotrophins and their Trk receptors play a crucial role in the development and maintenance of the vertebrate nervous system, but to date no component of this signalling system has been found in invertebrates. We describe a molluscan Trk receptor, designated Ltrk, from the snail Lymnaea stagnalis. The full-length sequence of Ltrk reveals most of the characteristics typical of Trk receptors, including highly conserved transmembrane and intracellular tyrosine kinase domains, and a typical extracellular domain of leucine-rich motifs flanked by cysteine clusters. In addition, Ltrk has a unique N-terminal extension and lacks immunoglobulin-like domains. Ltrk is expressed during development in a stage-specific manner, and also in the adult, where its expression is confined to the central nervous system and its associated endocrine tissues. Ltrk has the highest sequence identity with the TrkC mammalian receptor and, when exogenously expressed in fibroblasts or COS cells, binds human NT-3, but not NGF or BDNF, with an affinity of 2.5 nM. These findings support an early evolutionary origin of the Trk family as neuronal receptor tyrosine kinases and suggest that Trk signalling mechanisms may be highly conserved between vertebrates and invertebrates.

Full Text

The Full Text of this article is available as a PDF (252.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Altschul S. F., Gish W., Miller W., Myers E. W., Lipman D. J. Basic local alignment search tool. J Mol Biol. 1990 Oct 5;215(3):403–410. doi: 10.1016/S0022-2836(05)80360-2. [DOI] [PubMed] [Google Scholar]
  2. Barbacid M. The Trk family of neurotrophin receptors. J Neurobiol. 1994 Nov;25(11):1386–1403. doi: 10.1002/neu.480251107. [DOI] [PubMed] [Google Scholar]
  3. Barde Y. A. Neurotrophic factors: an evolutionary perspective. J Neurobiol. 1994 Nov;25(11):1329–1333. doi: 10.1002/neu.480251102. [DOI] [PubMed] [Google Scholar]
  4. Boer H. H., Montagne-Wajer C., Smith F. G., Parish D. C., Ramkema M. D., Hoek R. M., van Minnen J., Benjamin P. R. Functional morphology of the light yellow cell and yellow cell (sodium influx-stimulating peptide) neuroendocrine systems of the pond snail Lymnaea stagnalis. Cell Tissue Res. 1994 Feb;275(2):361–368. doi: 10.1007/BF00319435. [DOI] [PubMed] [Google Scholar]
  5. Bulloch A. G., Syed N. I. Reconstruction of neuronal networks in culture. Trends Neurosci. 1992 Nov;15(11):422–427. doi: 10.1016/0166-2236(92)90004-r. [DOI] [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Croll R. P., Chiasson B. J. Postembryonic development of serotoninlike immunoreactivity in the central nervous system of the snail, Lymnaea stagnalis. J Comp Neurol. 1989 Feb 1;280(1):122–142. doi: 10.1002/cne.902800109. [DOI] [PubMed] [Google Scholar]
  8. Darnell J. E., Jr Phosphotyrosine signaling and the single cell:metazoan boundary. Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):11767–11769. doi: 10.1073/pnas.94.22.11767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fainzilber M., Smit A. B., Syed N. I., Wildering W. C., Hermann, van der Schors R. C., Jiménez C., Li K. W., van Minnen J., Bulloch A. G. CRNF, a molluscan neurotrophic factor that interacts with the p75 neurotrophin receptor. Science. 1996 Nov 29;274(5292):1540–1543. doi: 10.1126/science.274.5292.1540. [DOI] [PubMed] [Google Scholar]
  10. Geraerts W. P., Algera L. H. The stimulating effect of the dorsal-body hormone on cell differentiation in the female accessory sex organs of the hermaphrodite freshwater snail, Lymnaea stagnalis. Gen Comp Endocrinol. 1976 May;29(1):109–118. doi: 10.1016/0016-6480(76)90012-5. [DOI] [PubMed] [Google Scholar]
  11. Geraerts W. P., Joosse J. Control of vitellogenesis and of growth of female accessory sex organs by the dorsal body hormone (DBH) in the hermaphroditic freshwater snail Lymnaea stagnalis. Gen Comp Endocrinol. 1975 Dec;27(4):450–464. doi: 10.1016/0016-6480(75)90065-9. [DOI] [PubMed] [Google Scholar]
  12. Greene L. A., Kaplan D. R. Early events in neurotrophin signalling via Trk and p75 receptors. Curr Opin Neurobiol. 1995 Oct;5(5):579–587. doi: 10.1016/0959-4388(95)80062-x. [DOI] [PubMed] [Google Scholar]
  13. Higgins D. G., Bleasby A. J., Fuchs R. CLUSTAL V: improved software for multiple sequence alignment. Comput Appl Biosci. 1992 Apr;8(2):189–191. doi: 10.1093/bioinformatics/8.2.189. [DOI] [PubMed] [Google Scholar]
  14. Holden P. H., Asopa V., Robertson A. G., Clarke A. R., Tyler S., Bennett G. S., Brain S. D., Wilcock G. K., Allen S. J., Smith S. K. Immunoglobulin-like domains define the nerve growth factor binding site of the TrkA receptor. Nat Biotechnol. 1997 Jul;15(7):668–672. doi: 10.1038/nbt0797-668. [DOI] [PubMed] [Google Scholar]
  15. Jing S., Tapley P., Barbacid M. Nerve growth factor mediates signal transduction through trk homodimer receptors. Neuron. 1992 Dec;9(6):1067–1079. doi: 10.1016/0896-6273(92)90066-m. [DOI] [PubMed] [Google Scholar]
  16. Jonas E. A., Knox R. J., Kaczmarek L. K., Schwartz J. H., Solomon D. H. Insulin receptor in Aplysia neurons: characterization, molecular cloning, and modulation of ion currents. J Neurosci. 1996 Mar 1;16(5):1645–1658. doi: 10.1523/JNEUROSCI.16-05-01645.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kaplan D. R., Miller F. D. Signal transduction by the neurotrophin receptors. Curr Opin Cell Biol. 1997 Apr;9(2):213–221. doi: 10.1016/s0955-0674(97)80065-8. [DOI] [PubMed] [Google Scholar]
  18. Korsching S. The neurotrophic factor concept: a reexamination. J Neurosci. 1993 Jul;13(7):2739–2748. doi: 10.1523/JNEUROSCI.13-07-02739.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kozak M. An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 1987 Oct 26;15(20):8125–8148. doi: 10.1093/nar/15.20.8125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lamballe F., Klein R., Barbacid M. trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell. 1991 Sep 6;66(5):967–979. doi: 10.1016/0092-8674(91)90442-2. [DOI] [PubMed] [Google Scholar]
  21. Lewin G. R., Barde Y. A. Physiology of the neurotrophins. Annu Rev Neurosci. 1996;19:289–317. doi: 10.1146/annurev.ne.19.030196.001445. [DOI] [PubMed] [Google Scholar]
  22. Lindsay R. M., Wiegand S. J., Altar C. A., DiStefano P. S. Neurotrophic factors: from molecule to man. Trends Neurosci. 1994 May;17(5):182–190. doi: 10.1016/0166-2236(94)90099-x. [DOI] [PubMed] [Google Scholar]
  23. MacDonald J. I., Meakin S. O. Deletions in the extracellular domain of rat trkA lead to an altered differentiative phenotype in neurotrophin responsive cells. Mol Cell Neurosci. 1996 May;7(5):371–390. doi: 10.1006/mcne.1996.0027. [DOI] [PubMed] [Google Scholar]
  24. Markussen F. H., Michon A. M., Breitwieser W., Ephrussi A. Translational control of oskar generates short OSK, the isoform that induces pole plasma assembly. Development. 1995 Nov;121(11):3723–3732. doi: 10.1242/dev.121.11.3723. [DOI] [PubMed] [Google Scholar]
  25. Meakin S. O., Shooter E. M. The nerve growth factor family of receptors. Trends Neurosci. 1992 Sep;15(9):323–331. doi: 10.1016/0166-2236(92)90047-c. [DOI] [PubMed] [Google Scholar]
  26. Meakin S. O., Suter U., Drinkwater C. C., Welcher A. A., Shooter E. M. The rat trk protooncogene product exhibits properties characteristic of the slow nerve growth factor receptor. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2374–2378. doi: 10.1073/pnas.89.6.2374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Merlio J. P., Ernfors P., Jaber M., Persson H. Molecular cloning of rat trkC and distribution of cells expressing messenger RNAs for members of the trk family in the rat central nervous system. Neuroscience. 1992 Dec;51(3):513–532. doi: 10.1016/0306-4522(92)90292-a. [DOI] [PubMed] [Google Scholar]
  28. Middlemas D. S., Lindberg R. A., Hunter T. trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol Cell Biol. 1991 Jan;11(1):143–153. doi: 10.1128/mcb.11.1.143-153.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ninkina N., Grashchuck M., Buchman V. L., Davies A. M. TrkB variants with deletions in the leucine-rich motifs of the extracellular domain. J Biol Chem. 1997 May 16;272(20):13019–13025. doi: 10.1074/jbc.272.20.13019. [DOI] [PubMed] [Google Scholar]
  30. Oishi I., Sugiyama S., Liu Z. J., Yamamura H., Nishida Y., Minami Y. A novel Drosophila receptor tyrosine kinase expressed specifically in the nervous system. Unique structural features and implication in developmental signaling. J Biol Chem. 1997 May 2;272(18):11916–11923. doi: 10.1074/jbc.272.18.11916. [DOI] [PubMed] [Google Scholar]
  31. Pulido D., Campuzano S., Koda T., Modolell J., Barbacid M. Dtrk, a Drosophila gene related to the trk family of neurotrophin receptors, encodes a novel class of neural cell adhesion molecule. EMBO J. 1992 Feb;11(2):391–404. doi: 10.1002/j.1460-2075.1992.tb05067.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Pérez P., Coll P. M., Hempstead B. L., Martín-Zanca D., Chao M. V. NGF binding to the trk tyrosine kinase receptor requires the extracellular immunoglobulin-like domains. Mol Cell Neurosci. 1995 Apr;6(2):97–105. doi: 10.1006/mcne.1995.1010. [DOI] [PubMed] [Google Scholar]
  33. Ridgway R. L., Syed N. I., Lukowiak K., Bulloch A. G. Nerve growth factor (NGF) induces sprouting of specific neurons of the snail, Lymnaea stagnalis. J Neurobiol. 1991 Jun;22(4):377–390. doi: 10.1002/neu.480220406. [DOI] [PubMed] [Google Scholar]
  34. Roovers E., Vincent M. E., van Kesteren E., Geraerts W. P., Planta R. J., Vreugdenhil E., van Heerikhuizen H. Characterization of a putative molluscan insulin-related peptide receptor. Gene. 1995 Sep 11;162(2):181–188. doi: 10.1016/0378-1119(95)00323-x. [DOI] [PubMed] [Google Scholar]
  35. Rydén M., Hempstead B., Ibáez C. F. Differential modulation of neuron survival during development by nerve growth factor binding to the p75 neurotrophin receptor. J Biol Chem. 1997 Jun 27;272(26):16322–16328. doi: 10.1074/jbc.272.26.16322. [DOI] [PubMed] [Google Scholar]
  36. Rydén M., Murray-Rust J., Glass D., Ilag L. L., Trupp M., Yancopoulos G. D., McDonald N. Q., Ibáez C. F. Functional analysis of mutant neurotrophins deficient in low-affinity binding reveals a role for p75LNGFR in NT-4 signalling. EMBO J. 1995 May 1;14(9):1979–1990. doi: 10.1002/j.1460-2075.1995.tb07190.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Schlessinger J., Ullrich A. Growth factor signaling by receptor tyrosine kinases. Neuron. 1992 Sep;9(3):383–391. doi: 10.1016/0896-6273(92)90177-f. [DOI] [PubMed] [Google Scholar]
  38. Smit A. B., Jiménez C. R., Dirks R. W., Croll R. P., Geraerts W. P. Characterization of a cDNA clone encoding multiple copies of the neuropeptide APGWamide in the mollusk Lymnaea stagnalis. J Neurosci. 1992 May;12(5):1709–1715. doi: 10.1523/JNEUROSCI.12-05-01709.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Smit A. B., Thijsen S. F., Geraerts W. P. cDNA cloning of the sodium-influx-stimulating peptide in the mollusc, Lymnaea stagnalis. Eur J Biochem. 1993 Jul 15;215(2):397–400. doi: 10.1111/j.1432-1033.1993.tb18046.x. [DOI] [PubMed] [Google Scholar]
  40. Smit A. B., Vreugdenhil E., Ebberink R. H., Geraerts W. P., Klootwijk J., Joosse J. Growth-controlling molluscan neurons produce the precursor of an insulin-related peptide. Nature. 1988 Feb 11;331(6156):535–538. doi: 10.1038/331535a0. [DOI] [PubMed] [Google Scholar]
  41. Songyang Z., Shoelson S. E., Chaudhuri M., Gish G., Pawson T., Haser W. G., King F., Roberts T., Ratnofsky S., Lechleider R. J. SH2 domains recognize specific phosphopeptide sequences. Cell. 1993 Mar 12;72(5):767–778. doi: 10.1016/0092-8674(93)90404-e. [DOI] [PubMed] [Google Scholar]
  42. Stephens R. M., Loeb D. M., Copeland T. D., Pawson T., Greene L. A., Kaplan D. R. Trk receptors use redundant signal transduction pathways involving SHC and PLC-gamma 1 to mediate NGF responses. Neuron. 1994 Mar;12(3):691–705. doi: 10.1016/0896-6273(94)90223-2. [DOI] [PubMed] [Google Scholar]
  43. Syed N., Richardson P., Bulloch A. Ciliary neurotrophic factor, unlike nerve growth factor, supports neurite outgrowth but not synapse formation by adult Lymnaea neurons. J Neurobiol. 1996 Mar;29(3):293–303. doi: 10.1002/(SICI)1097-4695(199603)29:3<293::AID-NEU2>3.0.CO;2-4. [DOI] [PubMed] [Google Scholar]
  44. Tensen C. P., Coenen T., van Herp F. Detection of mRNA encoding crustacean hyperglycemic hormone (CHH) in the eyestalk of the crayfish Orconectes limosus using non-radioactive in situ hybridization. Neurosci Lett. 1991 Apr 1;124(2):178–182. doi: 10.1016/0304-3940(91)90088-b. [DOI] [PubMed] [Google Scholar]
  45. Urfer R., Tsoulfas P., O'Connell L., Shelton D. L., Parada L. F., Presta L. G. An immunoglobulin-like domain determines the specificity of neurotrophin receptors. EMBO J. 1995 Jun 15;14(12):2795–2805. doi: 10.1002/j.1460-2075.1995.tb07279.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Weiss K. R., Brezina V., Cropper E. C., Hooper S. L., Miller M. W., Probst W. C., Vilim F. S., Kupfermann I. Peptidergic co-transmission in Aplysia: functional implications for rhythmic behaviors. Experientia. 1992 May 15;48(5):456–463. doi: 10.1007/BF01928164. [DOI] [PubMed] [Google Scholar]
  47. Wildering W. C., Lodder J. C., Kits K. S., Bulloch A. G. Nerve growth factor (NGF) acutely enhances high-voltage-activated calcium currents in molluscan neurons. J Neurophysiol. 1995 Dec;74(6):2778–2781. doi: 10.1152/jn.1995.74.6.2778. [DOI] [PubMed] [Google Scholar]
  48. Wilson C., Goberdhan D. C., Steller H. Dror, a potential neurotrophic receptor gene, encodes a Drosophila homolog of the vertebrate Ror family of Trk-related receptor tyrosine kinases. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7109–7113. doi: 10.1073/pnas.90.15.7109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Windisch J. M., Auer B., Marksteiner R., Lang M. E., Schneider R. Specific neurotrophin binding to leucine-rich motif peptides of TrkA and TrkB. FEBS Lett. 1995 Oct 23;374(1):125–129. doi: 10.1016/0014-5793(95)01047-i. [DOI] [PubMed] [Google Scholar]
  50. Windisch J. M., Marksteiner R., Lang M. E., Auer B., Schneider R. Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 bind to a single leucine-rich motif of TrkB. Biochemistry. 1995 Sep 5;34(35):11256–11263. doi: 10.1021/bi00035a035. [DOI] [PubMed] [Google Scholar]
  51. Windisch J. M., Marksteiner R., Schneider R. Nerve growth factor binding site on TrkA mapped to a single 24-amino acid leucine-rich motif. J Biol Chem. 1995 Nov 24;270(47):28133–28138. doi: 10.1074/jbc.270.47.28133. [DOI] [PubMed] [Google Scholar]
  52. de With N. D., van der Schors R. C., Boer H. H., Ebberink R. H. The sodium influx stimulating peptide of the pulmonate freshwater snail Lymnaea stagnalis. Peptides. 1993 Jul-Aug;14(4):783–789. doi: 10.1016/0196-9781(93)90114-v. [DOI] [PubMed] [Google Scholar]
  53. van der Geer P., Wiley S., Lai V. K., Olivier J. P., Gish G. D., Stephens R., Kaplan D., Shoelson S., Pawson T. A conserved amino-terminal Shc domain binds to phosphotyrosine motifs in activated receptors and phosphopeptides. Curr Biol. 1995 Apr 1;5(4):404–412. doi: 10.1016/s0960-9822(95)00081-9. [DOI] [PubMed] [Google Scholar]
  54. von Heijne G. A new method for predicting signal sequence cleavage sites. Nucleic Acids Res. 1986 Jun 11;14(11):4683–4690. doi: 10.1093/nar/14.11.4683. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES