Sistema de Salut de Catalunya
[Alvarez-Palomo B, Sarret H, Requena J] Molecular Genetics and Control of Pluripotency Laboratory, Department of Biomedicine, Biomedical Research Institute August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Institute of Neurosciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain. [Barrot-Feixat C] Forensic Genetics Laboratory, Medicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain. [Pau M] Molecular Genetics Laboratory, Department of Biomedicine, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain. [Vidal-Taboada JM] Recerca en Sistema Nerviós Perifèric, Servei de Neurociència, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
2020-09-08T07:36:02Z
2020-09-08T07:36:02Z
2019-10-08
SRC activation; Fertility; Mature testis
Activación de SRC; Fertilidad; Testículo maduro
Activació SRC; Fertilitat; Testicle madur
The vascular endothelial growth factor receptor 1 (VEGFR-1) family of receptors is preferentially expressed in endothelial cells, with the full-length and mostly the soluble (sVEGFR-1) isoforms being the most expressed ones. Surprisingly, cancer cells (MDA-MB-231) express, instead, alternative intracellular VEGFR-1 variants. We wondered if these variants, that are no longer dependent on ligands for activation, were expressed in a physiological context, specifically in spermatogenic cells, and whether their expression was maintained in spermatozoa and required for human fertility. By interrogating a human library of mature testis cDNA, we characterized two new truncated intracellular variants different from the ones previously described in cancer cells. The new isoforms were transcribed from alternative transcription start sites (aTSS) located respectively in intron-19 (i19VEGFR-1) and intron-28 (i28VEGFR-1) of the VEGFR-1 gene (GenBank accession numbers JF509744 and JF509745) and expressed in mature testis and spermatozoa. In this paper, we describe the characterization of these isoforms by RT-PCR, northern blot, and western blot, their preferential expression in human mature testis and spermatozoa, and the elements that punctuate their proximal promoters and suggest cues for their expression in spermatogenic cells. Mechanistically, we show that i19VEGFR-1 has a strong ability to phosphorylate and activate SRC proto-oncogene non-receptor tyrosine kinases and a significant bias toward a decrease in expression in patients considered infertile by WHO criteria.
This study was supported by the University of Barcelona, MINECO project grant BFU2014-54467-P.
Article
Published version
English
Esterilitat masculina; Genètica - Tècnica; Endoteli vascular; DISEASES::Male Urogenital Diseases::Genital Diseases, Male::Infertility::Infertility, Male; ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Investigative Techniques::Genetic Techniques; CHEMICALS AND DRUGS::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Tyrosine Kinases::Receptor Protein-Tyrosine Kinases::Receptors, Vascular Endothelial Growth Factor::Vascular Endothelial Growth Factor Receptor-1; ENFERMEDADES::enfermedades urogenitales masculinas::enfermedades de los genitales masculinos::infertilidad::infertilidad masculina; TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::técnicas de investigación::técnicas genéticas; COMPUESTOS QUÍMICOS Y DROGAS::enzimas y coenzimas::enzimas::transferasas::fosfotransferasas::fosfotransferasas (grupo alcohol aceptor)::proteína cinasas::proteína-tirosina cinasas::receptores proteína-tirosina cinasas::receptores del factor de crecimiento del endotelio vascular::receptor 1 de factores de crecimiento endotelial vascular
Impact Journals
Oncotarget;10(56)
https://www.oncotarget.com/article/27232/text/
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
Articles científics - VHIR [1655]
