Two novel ligand-independent variants of the VEGFR-1 receptor are expressed in human testis and spermatozoa, one of them with the ability to activate SRC proto-oncogene tyrosine kinases
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Belen Alvarez-Palomo1,*, Carme Barrot-Feixat2,*, Helena Sarret1, Jordi Requena1, Montserrat Pau3, Jose-Manuel Vidal-Taboada4, Rafael Oliva5,6, Josep-Lluis Ballesca7, Michael J. Edel1,8,9 and Jovita Mezquita-Pla1
1 Molecular Genetics and Control of Pluripotency Laboratory, Department of Biomedicine, Biomedical Research Institute August Pi i Sunyer (IDIBAPS), Institute of Neurosciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, Spain
2 Forensic Genetics Laboratory, Medicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, Spain
3 Molecular Genetics Laboratory, Department of Biomedicine, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, Spain
4 Peripheral Nervous System, Neuroscience Department, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain
5 Molecular Biology of Reproduction and Development Laboratory, Biomedical Research Institute August Pi i Sunyer (IDIBAPS), Department of Biomedicine, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, Spain
6 Biochemistry and Molecular Genetics Service, Biomedical Diagnostic Centre, Hospital Clinic, Barcelona, Catalonia, Spain
7 Clinic Institute of Gynaecology, Obstetrics and Neonatology, Hospital Clinic, Barcelona, Catalonia, Spain
8 International Research Fellow, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
9 Senior Research Fellow, University of Western Australia, School of Medicine and Pharmacology, Harry Perkins Research Institute Centre for Cell Therapy and Regenerative Medicine (CCTRM), Perth, Western Australia, Australia
* First authors
Keywords: ligand-independent intracellular iVEGFR-1 isoforms; mature testis; spermiogenesis; SRC activation; fertility
Received: July 17, 2019 Accepted: September 24, 2019 Published: October 08, 2019
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.
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