Signal Transduction Mediated by the Truncated trkB Receptor Isoforms, trkB.T1 and trkB.T2

Abstract

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 ligandbinding 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.

Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence

“…[13][14][15][16] However, there is accumulating evidence that truncated TrkB isoforms have both dominant-negative inhibitory activity on full-length TrkB receptors and yet are capable of mediating signal transduction independent of full-length TrkB receptors. 14,15,17,18 Evidence supporting a role for BDNF signaling in mechanisms of alcohol and drug dependence has been well documented using different animal models. For example, McGough et al 19 showed that in BDNF-deficient mice, decreased levels of BDNF lead to increased ethanol sensitization and increased voluntary ethanol consumption after a 2-week withdrawal compared to wild-type animals.…”

Expression of the naturally occurring truncated trkB neurotrophin receptor induces outgrowth of filopodia and processes in neuroblastoma cells

“…Rubio (1997) has shown that astrocytes use truncated trkB to take up, store and deliver BDNF in intact, biologically active form. Recently, Baxter et al (1997) have provided evidence that trkB.TK7 receptors may induce signal transduction on their own by causing ligand-dependent acidi®cation determined by a cytosensor device. These observations raise the possibility that trkB.TK7 isoforms may have an active role in shaping the response to neurotrophins.…”

Neurotrophins and B-cell malignancies

“…They also found that K252a treatment of OCI-LY3 cells resulted in inhibition of NF-κB transcriptional activity with a concomitant decrease in IL-6 production , which may act as an autocrine/paracrine pro-survival signal [127]. It is likely that K252a is targeting TrkC signaling in these cells as it is unable to fully inhibit TrkB 95 [128]. This signifies a possible avenue of investigation into new targeted therapies for DLBCL.…”

“…No data No data p75 NTR Murine spleen and bone marrow [108] resting and activated human B cells [104] memory-like B cell line [105] Apoptosis induction (by pro-BDNF) in a mature B cell line (BL2) in vitro [106] sortilin B cell lines [106] Apoptosis induction of a mature B cell line (BL20) [106] Pro-NT-3 expressed intracellularly in OCI-LY3 and OCI-LY19 cell lines [126] NT-3 secreted by OCI-LY3 and OCI-LY19 cell lines [126] mRNA expressed in all patient samples [126] NT-4/5 TrkA Expressed in OCI-LY19 cell line [126] Expressed in patient samples [126] TrkB 145 Not detected in SUDHL4, SUDHL6, OCI-LY3 or OCI-LY19 cell lines [125,126] [123] Expressed in SUDHL4 and SUDHL6 cell lines, upregulated on stress [125] Not detected in any cell lines tested [129] Not detected at mRNA or protein level in patient samples [129] sortilin mRNA and protein expressed in RS4 and Nalm6 cell line [124,128] Low membranous expression, increased on stress in Nalm6 cell line [124] Expressed in SUDHL4 and SUDHL6 cell lines [125] mRNA and protein expressed in BL2 and BL41 cell lines [124,106], increased on stress [124] Low membranous expression, increased on stress in BL41 cell line [124] mRNA and protein expressed in U266 and RPMI-8226 cell lines [124,128], increased on stress [124] Membranous expression increased on stress in RPMI-8226 cell line [124] Induces apoptosis in response to pro-BDNF in U266 and RPMI-8226 cell lines via [106] …”