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. 1996 Jul 1;15(13):3332–3337.

A splice variant of the neurotrophin receptor trkB with increased specificity for brain-derived neurotrophic factor.

C Strohmaier 1, B D Carter 1, R Urfer 1, Y A Barde 1, G Dechant 1
PMCID: PMC451896  PMID: 8670834

Abstract

The trkB gene codes for a receptor tyrosine kinase, which is essential for the development of the peripheral nervous system. This receptor can be activated by three different neurotrophins: BDNF, NT-4/5 and NT-3. The extracellular domain of trkB was found to be encoded in 10 exons corresponding to receptor subdomains previously identified on the basis of protein sequence comparisons. Exon 9 was skipped in a novel tyrosine kinase transcript of the trkB gene, designated ctrkB-Short (ctrkB-S). While the previously described trkB receptor ctrkB-Long (ctrkB-L) and trkB-S receptors were activated similarly by BDNF, trkB-S interacted poorly with NT-4/5 and NT-3 as measured by ligand binding, ligand-induced autophosphorylation and ligand-dependent activation of p21ras. Efficient activation of ctrkB-S by NT-3 was restored by a single amino acid replacement in NT-3 (D15A). Both trkB-L and trkB-S transcripts were detected in embryonic neurons.

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Selected References

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

  1. Andersson S., Davis D. L., Dahlbäck H., Jörnvall H., Russell D. W. Cloning, structure, and expression of the mitochondrial cytochrome P-450 sterol 26-hydroxylase, a bile acid biosynthetic enzyme. J Biol Chem. 1989 May 15;264(14):8222–8229. [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. Barker P. A., Lomen-Hoerth C., Gensch E. M., Meakin S. O., Glass D. J., Shooter E. M. Tissue-specific alternative splicing generates two isoforms of the trkA receptor. J Biol Chem. 1993 Jul 15;268(20):15150–15157. [PubMed] [Google Scholar]
  4. Carter B. D., Zirrgiebel U., Barde Y. A. Differential regulation of p21ras activation in neurons by nerve growth factor and brain-derived neurotrophic factor. J Biol Chem. 1995 Sep 15;270(37):21751–21757. doi: 10.1074/jbc.270.37.21751. [DOI] [PubMed] [Google Scholar]
  5. Chen C., Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. doi: 10.1128/mcb.7.8.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Clary D. O., Reichardt L. F. An alternatively spliced form of the nerve growth factor receptor TrkA confers an enhanced response to neurotrophin 3. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11133–11137. doi: 10.1073/pnas.91.23.11133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Davies A. M., Minichiello L., Klein R. Developmental changes in NT3 signalling via TrkA and TrkB in embryonic neurons. EMBO J. 1995 Sep 15;14(18):4482–4489. doi: 10.1002/j.1460-2075.1995.tb00127.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dechant G., Biffo S., Okazawa H., Kolbeck R., Pottgiesser J., Barde Y. A. Expression and binding characteristics of the BDNF receptor chick trkB. Development. 1993 Oct;119(2):545–558. doi: 10.1242/dev.119.2.545. [DOI] [PubMed] [Google Scholar]
  9. Götz R., Kolbeck R., Lottspeich F., Barde Y. A. Production and characterization of recombinant mouse neurotrophin-3. Eur J Biochem. 1992 Mar 1;204(2):745–749. doi: 10.1111/j.1432-1033.1992.tb16689.x. [DOI] [PubMed] [Google Scholar]
  10. Ip N. Y., Ibáez C. F., Nye S. H., McClain J., Jones P. F., Gies D. R., Belluscio L., Le Beau M. M., Espinosa R., 3rd, Squinto S. P. Mammalian neurotrophin-4: structure, chromosomal localization, tissue distribution, and receptor specificity. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3060–3064. doi: 10.1073/pnas.89.7.3060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Johnson D. E., Williams L. T. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res. 1993;60:1–41. doi: 10.1016/s0065-230x(08)60821-0. [DOI] [PubMed] [Google Scholar]
  12. Kaplan D. R., Stephens R. M. Neurotrophin signal transduction by the Trk receptor. J Neurobiol. 1994 Nov;25(11):1404–1417. doi: 10.1002/neu.480251108. [DOI] [PubMed] [Google Scholar]
  13. Klein R., Conway D., Parada L. F., Barbacid M. The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Cell. 1990 May 18;61(4):647–656. doi: 10.1016/0092-8674(90)90476-u. [DOI] [PubMed] [Google Scholar]
  14. Klein R., Lamballe F., Bryant S., Barbacid M. The trkB tyrosine protein kinase is a receptor for neurotrophin-4. Neuron. 1992 May;8(5):947–956. doi: 10.1016/0896-6273(92)90209-v. [DOI] [PubMed] [Google Scholar]
  15. Klein R., Smeyne R. J., Wurst W., Long L. K., Auerbach B. A., Joyner A. L., Barbacid M. Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death. Cell. 1993 Oct 8;75(1):113–122. [PubMed] [Google Scholar]
  16. Kolbeck R., Jungbluth S., Barde Y. A. Characterisation of neurotrophin dimers and monomers. Eur J Biochem. 1994 Nov 1;225(3):995–1003. doi: 10.1111/j.1432-1033.1994.0995b.x. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. McAllister A. K., Lo D. C., Katz L. C. Neurotrophins regulate dendritic growth in developing visual cortex. Neuron. 1995 Oct;15(4):791–803. doi: 10.1016/0896-6273(95)90171-x. [DOI] [PubMed] [Google Scholar]
  19. McDonald N. Q., Lapatto R., Murray-Rust J., Gunning J., Wlodawer A., Blundell T. L. New protein fold revealed by a 2.3-A resolution crystal structure of nerve growth factor. Nature. 1991 Dec 5;354(6352):411–414. doi: 10.1038/354411a0. [DOI] [PubMed] [Google Scholar]
  20. 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Rodriguez-Tébar A., Barde Y. A. Binding characteristics of brain-derived neurotrophic factor to its receptors on neurons from the chick embryo. J Neurosci. 1988 Sep;8(9):3337–3342. doi: 10.1523/JNEUROSCI.08-09-03337.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Schneider R., Schweiger M. A novel modular mosaic of cell adhesion motifs in the extracellular domains of the neurogenic trk and trkB tyrosine kinase receptors. Oncogene. 1991 Oct;6(10):1807–1811. [PubMed] [Google Scholar]
  25. Schröpel A., von Schack D., Dechant G., Barde Y. A. Early expression of the nerve growth factor receptor ctrkA in chick sympathetic and sensory ganglia. Mol Cell Neurosci. 1995 Dec;6(6):544–566. doi: 10.1006/mcne.1995.0006. [DOI] [PubMed] [Google Scholar]
  26. Shelton D. L., Sutherland J., Gripp J., Camerato T., Armanini M. P., Phillips H. S., Carroll K., Spencer S. D., Levinson A. D. Human trks: molecular cloning, tissue distribution, and expression of extracellular domain immunoadhesins. J Neurosci. 1995 Jan;15(1 Pt 2):477–491. doi: 10.1523/JNEUROSCI.15-01-00477.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Snider W. D. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell. 1994 Jun 3;77(5):627–638. doi: 10.1016/0092-8674(94)90048-5. [DOI] [PubMed] [Google Scholar]
  28. Studer L., Spenger C., Seiler R. W., Altar C. A., Lindsay R. M., Hyman C. Comparison of the effects of the neurotrophins on the morphological structure of dopaminergic neurons in cultures of rat substantia nigra. Eur J Neurosci. 1995 Feb 1;7(2):223–233. doi: 10.1111/j.1460-9568.1995.tb01058.x. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Urfer R., Tsoulfas P., Soppet D., Escandón E., Parada L. F., Presta L. G. The binding epitopes of neurotrophin-3 to its receptors trkC and gp75 and the design of a multifunctional human neurotrophin. EMBO J. 1994 Dec 15;13(24):5896–5909. doi: 10.1002/j.1460-2075.1994.tb06935.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Vinh N. Q., Erdmann K. S., Heumann R. Cloning and sequence analysis of a cDNA encoding a novel truncated form of the chicken TrkB receptor. Gene. 1994 Nov 18;149(2):383–384. doi: 10.1016/0378-1119(94)90184-8. [DOI] [PubMed] [Google Scholar]
  32. 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]

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