Abstract
Teneurins are large type II transmembrane proteins that are necessary for the normal development of the CNS. Although many studies highlight the significance of teneurins, especially during development, there is only limited information known about the molecular mechanisms of function. Previous studies have shown that the N-terminal intracellular domain (ICD) of teneurins can be cleaved at the membrane and subsequently translocates to the nucleus, where it can influence gene transcription. Because teneurin ICDs do not contain any intrinsic DNA binding sequences, interaction partners are required to affect transcription. Here, we identified histidine triad nucleotide binding protein 1 (HINT1) as a human teneurin-1 ICD interaction partner in a yeast two-hybrid screen. This interaction was confirmed in human cells, where HINT1 is known to inhibit the transcription of target genes by directly binding to transcription factors at the promoter. In a whole transcriptome analysis of BS149 glioblastoma cells overexpressing the teneurin-1 ICD, several microphthalmia-associated transcription factor (MITF) target genes were found to be up-regulated. Directly comparing the transcriptomes of MITF versus TEN1-ICD-overexpressing BS149 cells revealed 42 co-regulated genes, including glycoprotein non-metastatic b (GPNMB). Using real-time quantitative PCR to detect endogenous GPNMB expression upon overexpression of MITF and HINT1 as well as promoter reporter assays using GPNMB promoter constructs, we could demonstrate that the teneurin-1 ICD binds HINT1, thus switching on MITF-dependent transcription of GPNMB.
Highlights
The intracellular domain of teneurins translocates to the nucleus and is thought to influence transcription
histidine triad nucleotide binding protein 1 (HINT1) was one of the interaction partners found in the yeast two-hybrid screen described above, and we considered that this interaction may be involved in the induction of microphthalmia-associated transcription factor (MITF) target genes by the TEN1-intracellular domain (ICD)
We propose a function for the ICD of teneurin-1 that is very similar to the Notch signaling pathway
Summary
The intracellular domain of teneurins translocates to the nucleus and is thought to influence transcription. We identified histidine triad nucleotide binding protein 1 (HINT1) as a human teneurin-1 ICD interaction partner in a yeast two-hybrid screen This interaction was confirmed in human cells, where HINT1 is known to inhibit the transcription of target genes by directly binding to transcription factors at the promoter. Expression patterns during development taken together with functional studies strongly suggest a role for teneurins during development of the CNS in Drosophila (6 – 8), C. elegans [9, 10], chicken [6, 11,12,13,14,15], and mouse (5, 16 –19), teneurins are likely to play roles in other regions, like the developing limbs, as well [12, 13] Members of this protein family are type II transmembrane proteins containing a single-spanning transmembrane domain. The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession nos. 61704 and 61705)
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