title: Activation of mitogen-activated protein kinase kinase (MEK)/extracellular signal regulated kinase (ERK) signaling pathway is involved in myeloid lineage commitment.
abstract: Common lymphoid progenitors (CLPs) are lymphoid-lineage-committed progenitor cells. However, they maintain a latent myeloid differentiation potential that can be initiated by stimulation with interleukin-2 (IL-2) via ectopically expressed IL-2 receptors. Although CLPs express IL-7 receptors, which share the common gamma chain with IL-2 receptors, IL-7 cannot initiate lineage conversion in CLPs. In this study, we demonstrate that the critical signals for initiating lineage conversion in CLPs are delivered via IL-2 receptor beta (IL-2R beta) intracellular domains. Fusion of the A region of the IL-2R beta cytoplasmic tail to IL-7R alpha enables IL-7 to initiate myeloid differentiation in CLPs. We found that Shc, which associates with the A region, mediates lineage conversion signals through the mitogen activated protein kinase (MAPK) pathway. Because mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitors completely blocked IL-2-mediated lineage conversion, MAPK activation, specifically via the MEK/ERK pathway, is critically involved in the initiation of this event. Furthermore, formation of granulocyte/macrophage (GM) colonies by hematopoietic stem cells, but not by common myeloid progenitors (CMPs), was severely reduced in the presence of MEK/ERK inhibitors. These results demonstrate that activation of MEK/ERK plays an important role in GM lineage commitment.
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Hsu
authors.forename: Kazu
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Motonari
authors.initials: M
authors.lastname: Kondo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C508022:Il2rb protein, mouse; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; D047428:Protein Kinase Inhibitors; D020395:Receptors, Interleukin-7; D011993:Recombinant Fusion Proteins; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D048049:Extracellular Signal-Regulated MAP Kinases