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RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development
Ligation of erythropoietin (EPO) receptor (EPOR) JAK2 kinase complexes propagates signals within erythroid progenitor cells (EPCs) that are essential for red blood cell production. To reveal hypothesized novel EPOR/JAK2 targets, a phosphotyrosine (PY) phosphoproteomics approach was applied. Beyond k...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144737/ https://www.ncbi.nlm.nih.gov/pubmed/25092874 http://dx.doi.org/10.1084/jem.20130624 |
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author | Verma, Rakesh Su, Su McCrann, Donald J. Green, Jennifer M. Leu, Karen Young, Peter R. Schatz, Peter J. Silva, Jeffrey C. Stokes, Matthew P. Wojchowski, Don M. |
author_facet | Verma, Rakesh Su, Su McCrann, Donald J. Green, Jennifer M. Leu, Karen Young, Peter R. Schatz, Peter J. Silva, Jeffrey C. Stokes, Matthew P. Wojchowski, Don M. |
author_sort | Verma, Rakesh |
collection | PubMed |
description | Ligation of erythropoietin (EPO) receptor (EPOR) JAK2 kinase complexes propagates signals within erythroid progenitor cells (EPCs) that are essential for red blood cell production. To reveal hypothesized novel EPOR/JAK2 targets, a phosphotyrosine (PY) phosphoproteomics approach was applied. Beyond known signal transduction factors, 32 new targets of EPO-modulated tyrosine phosphorylation were defined. Molecular adaptors comprised one major set including growth factor receptor-bound protein 2 (GRB2)–associated binding proteins 1–3 (GAB1-3), insulin receptor substrate 2 (IRS2), docking protein 1 (DOK1), Src homology 2 domain containing transforming protein 1 (SHC1), and sprouty homologue 1 (SPRY1) as validating targets, and SPRY2, SH2 domain containing 2A (SH2D2A), and signal transducing adaptor molecule 2 (STAM2) as novel candidate adaptors together with an ORF factor designated as regulator of human erythroid cell expansion (RHEX). RHEX is well conserved in Homo sapiens and primates but absent from mouse, rat, and lower vertebrate genomes. Among tissues and lineages, RHEX was elevated in EPCs, occurred as a plasma membrane protein, was rapidly PY-phosphorylated >20-fold upon EPO exposure, and coimmunoprecipitated with the EPOR. In UT7epo cells, knockdown of RHEX inhibited EPO-dependent growth. This was associated with extracellular signal-regulated kinase 1,2 (ERK1,2) modulation, and RHEX coupling to GRB2. In primary human EPCs, shRNA knockdown studies confirmed RHEX regulation of erythroid progenitor expansion and further revealed roles in promoting the formation of hemoglobinizing erythroblasts. RHEX therefore comprises a new EPO/EPOR target and regulator of human erythroid cell expansion that additionally acts to support late-stage erythroblast development. |
format | Online Article Text |
id | pubmed-4144737 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-41447372015-02-25 RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development Verma, Rakesh Su, Su McCrann, Donald J. Green, Jennifer M. Leu, Karen Young, Peter R. Schatz, Peter J. Silva, Jeffrey C. Stokes, Matthew P. Wojchowski, Don M. J Exp Med Brief Definitive Report Ligation of erythropoietin (EPO) receptor (EPOR) JAK2 kinase complexes propagates signals within erythroid progenitor cells (EPCs) that are essential for red blood cell production. To reveal hypothesized novel EPOR/JAK2 targets, a phosphotyrosine (PY) phosphoproteomics approach was applied. Beyond known signal transduction factors, 32 new targets of EPO-modulated tyrosine phosphorylation were defined. Molecular adaptors comprised one major set including growth factor receptor-bound protein 2 (GRB2)–associated binding proteins 1–3 (GAB1-3), insulin receptor substrate 2 (IRS2), docking protein 1 (DOK1), Src homology 2 domain containing transforming protein 1 (SHC1), and sprouty homologue 1 (SPRY1) as validating targets, and SPRY2, SH2 domain containing 2A (SH2D2A), and signal transducing adaptor molecule 2 (STAM2) as novel candidate adaptors together with an ORF factor designated as regulator of human erythroid cell expansion (RHEX). RHEX is well conserved in Homo sapiens and primates but absent from mouse, rat, and lower vertebrate genomes. Among tissues and lineages, RHEX was elevated in EPCs, occurred as a plasma membrane protein, was rapidly PY-phosphorylated >20-fold upon EPO exposure, and coimmunoprecipitated with the EPOR. In UT7epo cells, knockdown of RHEX inhibited EPO-dependent growth. This was associated with extracellular signal-regulated kinase 1,2 (ERK1,2) modulation, and RHEX coupling to GRB2. In primary human EPCs, shRNA knockdown studies confirmed RHEX regulation of erythroid progenitor expansion and further revealed roles in promoting the formation of hemoglobinizing erythroblasts. RHEX therefore comprises a new EPO/EPOR target and regulator of human erythroid cell expansion that additionally acts to support late-stage erythroblast development. The Rockefeller University Press 2014-08-25 /pmc/articles/PMC4144737/ /pubmed/25092874 http://dx.doi.org/10.1084/jem.20130624 Text en © 2014 Verma et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Brief Definitive Report Verma, Rakesh Su, Su McCrann, Donald J. Green, Jennifer M. Leu, Karen Young, Peter R. Schatz, Peter J. Silva, Jeffrey C. Stokes, Matthew P. Wojchowski, Don M. RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development |
title | RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development |
title_full | RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development |
title_fullStr | RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development |
title_full_unstemmed | RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development |
title_short | RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development |
title_sort | rhex, a novel regulator of human erythroid progenitor cell expansion and erythroblast development |
topic | Brief Definitive Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144737/ https://www.ncbi.nlm.nih.gov/pubmed/25092874 http://dx.doi.org/10.1084/jem.20130624 |
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