{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRHEX is a novel, conserved plasma membrane adaptor protein that plays an essential role in erythropoietin (EPO) signaling within human erythroid progenitor cells. Upon EPO engagement, RHEX is robustly tyrosine phosphorylated (>20‐fold increase) and associates with the EPO receptor (EPOR), coupling with GRB2 to modulate downstream activation of ERK1/2. Functional studies using shRNA knockdown in erythroid progenitors revealed that loss of RHEX impairs EPO‐dependent cell expansion and disrupts the formation of hemoglobinizing erythroblasts, thereby establishing RHEX as a critical positive regulator of human erythroid cell proliferation and maturation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn contrast, investigation in mast cells has unveiled a distinctly different role for RHEX in this lineage. Highly expressed in both immature and mature skin mast cells, RHEX acts unexpectedly as a negative regulator of SCF/KIT-driven survival signaling. RNA interference studies demonstrated that attenuation of RHEX leads to enhanced activation of ERK1/2 and p38 MAP kinases as well as increased induction of immediate‐early genes such as NR4A2, JUNB, and EGR1. These results indicate that in mast cells, RHEX interferes with KIT signal transduction, thereby restraining cell survival pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these studies illustrate that RHEX functions as a context-dependent modulator of signal transduction within different hematopoietic lineages. While it promotes erythroid progenitor expansion and erythroblast development through facilitation of EPO/EPOR-ERK1/2 signaling, RHEX concurrently serves as a repressor of SCF/KIT-mediated activation in mast cells. This dual functionality underscores the importance of RHEX as a lineage-specific regulator, and further exploration of its roles may reveal novel targets for managing disorders associated with aberrant hematopoiesis and mast cell-related pathologies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Rakesh Verma, Su Su, Donald J McCrann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20130624"}], "href": "https://doi.org/10.1084/jem.20130624"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25092874"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25092874"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kristin Franke, Gürkan Bal, Zhuoran Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clorfl86/RHEX Is a Negative Regulator of SCF/KIT Signaling in Human Skin Mast Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cells (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/cells12091306"}], "href": "https://doi.org/10.3390/cells12091306"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37174705"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37174705"}]}]}]}