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Volume 17, Number 8, Issue of April 15, 1997 pp. 2683-2690
Copyright ©1997 Society for NeuroscienceSignal Transduction Mediated by the Truncated trkB Receptor Isoforms, trkB.T1 and trkB.T2
Received Sept. 26, 1996; revised Jan. 23, 1997; accepted Jan. 31, 1997.
Gregory T. Baxter1, Monte J. Radeke3, 4, Richard C. Kuo2, 3, Victoria Makrides3, 4, Beth Hinkle3, 4, Richard Hoang3, 4, Angelica Medina-Selby5, Doris Coit5, Pablo Valenzuela5, and Stuart C. Feinstein3, 4 1 Molecular Devices Corporation, Sunnyvale, California 94089, 2 Neurosciences Program, Stanford University School of Medicine, Stanford, California 94305, 3 Neuroscience Research Institute and 4 Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, California 93106, and 5 Chiron Corporation, Emeryville, California 94608-2916
The trkB family of transmembrane proteins serves as receptors for BDNF and NT-4/5. The family is composed of a tyrosine kinase-containing isoform as well as several alternatively spliced "truncated receptors" with identical extracellular ligand-binding domains but very small intracellular domains. The two best-characterized truncated trkB receptors, designated as trkB.T1 and trkB.T2, contain intracellular domains of only 23 and 21 amino acids, respectively. Although it is known that the tyrosine kinase isoform (trkB.FL) is capable of initiating BDNF and NT-4/5-induced signal transduction, the functional role or roles of the truncated receptors remain enigmatic. At the same time, the potential importance of the truncated receptors in the development, maintenance, and regeneration of the nervous system has been highlighted by recent developmental and injury paradigm investigations. Here we have used trkB cDNA transfected cell lines to demonstrate that both trkB.T1 and trkB.T2 are capable of mediating BDNF-induced signal transduction. More specifically, BDNF activation of either trkB.T1 or trkB.T2 increases the rate of acidic metabolite release from the cell, a common physiological consequence of many signaling pathways. Further, these trkB.T1- and trkB.T2-mediated changes occur with kinetics distinct from changes mediated by trkB.FL, suggesting the participation of at least some unique rate-limiting component or components. Mutational analysis demonstrates that the isoform-specific sequences within the intracellular domains of each receptor are essential for signaling capability. Finally, inhibitor studies suggest that kinases are likely to be involved in the trkB.T1 and trkB.T2 signaling pathways.
Key words: trkB; BDNF; NT4/5; neurotrophin; truncated receptors; signal transduction
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