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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2014
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.
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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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