Abstract
BackgroundTropomyosin-related kinase A (TRKA) is a nerve growth factor (NGF) receptor that belongs to the tyrosine kinase receptor family. It is critical for the correct development of many types of neurons including pain-mediating sensory neurons and also controls proliferation, differentiation and survival of many neuronal and non-neuronal cells. TRKA (also known as NTRK1) gene is a target of alternative splicing which can result in several different protein isoforms. Presently, three human isoforms (TRKAI, TRKAII and TRKAIII) and two rat isoforms (TRKA L0 and TRKA L1) have been described.ResultsWe show here that human TRKA gene is overlapped by two genes and spans 67 kb—almost three times the size that has been previously described. Numerous transcription initiation sites from eight different 5′ exons and a sophisticated splicing pattern among exons encoding the extracellular part of TRKA receptor indicate that there might be a large variety of alternative protein isoforms. TrkA genes in rat and mouse appear to be considerably shorter, are not overlapped by other genes and display more straightforward splicing patterns. We describe the expression profile of alternatively spliced TRKA transcripts in different tissues of human, rat and mouse, as well as analyze putative endogenous TRKA protein isoforms in human SH-SY5Y and rat PC12 cells. We also characterize a selection of novel putative protein isoforms by portraying their phosphorylation, glycosylation and intracellular localization patterns. Our findings show that an isoform comprising mainly of TRKA kinase domain is capable of entering the nucleus.ConclusionsResults obtained in this study refer to the existence of a multitude of TRKA mRNA and protein isoforms, with some putative proteins possessing very distinct properties.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-015-0215-x) contains supplementary material, which is available to authorized users.
Highlights
Tropomyosin-related kinase A (TRKA) is a nerve growth factor (NGF) receptor that belongs to the tyrosine kinase receptor family
An elaborate arrangement of the human TRKA gene revealed by novel transcription initiation sites In silico analysis of the human TRKA gene structure using UCSC genome browser [42] to align the TRKA mRNAs and expressed sequence tags (ESTs) from GenBank to the genomic sequence indicated a higher level of variability among TRKA transcripts and a longer span of the gene than previously described in the literature
From the information obtained of mRNAs, we predicted potential TRKA protein isoforms and named them in this study as follows: isoforms with different N-termini from the conventional TRKAII are named as α, β, γ, δ, ε, ζ, η, θ and κ (Fig. 1c), isoforms which lack different parts in their extracellular portion are distinguished with roman numerals I...IX (Fig. 1d; protein sequences are listed in Additional file 1)
Summary
Tropomyosin-related kinase A (TRKA) is a nerve growth factor (NGF) receptor that belongs to the tyrosine kinase receptor family. It is critical for the correct development of many types of neurons including pain-mediating sensory neurons and controls proliferation, differentiation and survival of many neuronal and non-neuronal cells. Several neurotrophin independent signaling events have been described, including transactivation of receptor tyrosine kinases by adenosine 2A receptors [9, 10], pituitary adenylate cyclase-activating polypeptide receptor [11], low-density lipoprotein receptor-related protein 1 [12], epidermal growth factor receptor [13] and antidepressants [14]
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