A KIT juxtamembrane PY567 -directed pathway provides nonredundant signals for erythroid progenitor cell development and stress erythropoiesis
| Autor: | Valter Agosti, Pradeep Sathyanarayana, Vinit Karur, Don M. Wojchowski, Peter Besmer |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Antimetabolites Antineoplastic Myeloid MAP Kinase Signaling System Mutation Missense Stem cell factor Biology Hemolysis Article Mice Erythroblast Stress Physiological Genetics medicine Animals Erythropoiesis Progenitor cell Molecular Biology Erythroid Precursor Cells Mice Knockout Stem Cell Factor Anemia Cell Biology Hematology Oxidants Molecular biology Cell biology Phenylhydrazines Proto-Oncogene Proteins c-kit medicine.anatomical_structure Amino Acid Substitution Erythropoietin Bone marrow Fluorouracil Protein Kinases medicine.drug |
| Popis: | Objective KITL/KIT can elicit diverse sets of signals within lymphoid, myeloid, mast, and erythroid lineages, and exert distinct effects on growth, survival, migration, adhesion, and secretory responses. Presently, we have applied a PY-mutant allele knockin approach to specifically assess possible roles for KIT-PY567 and KIT-PY719 sites, and coupled pathways, during erythropoiesis. Materials and Methods Mouse models used to investigate this problem include those harboring knocked-in KIT Y567F/Y567F , KIT Y569F/Y569F , KIT Y719F,Y719F , and KIT Y567F/Y567F:Y569F/Y569F alleles. The erythron was stressed by myelosuppression using 5-fluorouracil, and by phenylhydrazine-induced hemolysis. In addition, optimized systems for ex vivo analyses of bone marrow and splenic erythropoiesis were employed to more directly analyze possible stage-specific effects on erythroid cell growth, survival, development and KIT signaling events. Results In Kit Y567F/Y567F mice, steady-state erythropoiesis was unperturbed while recovery from anemia due to 5-fluorouracil or phenylhydrazine was markedly impaired. Deficiencies in erythroid progenitor expansion occurred both in the bone marrow and the spleen. Responses to chronic erythropoietin dosing were also compromised. Ex vivo, Kit Y567F/Y567F (pro)erythroblast development was skewed from a Kit pos CD71 high stage toward a subsequent Kit neg CD71 high compartment. Proliferation and, to an extent, survival capacities were also compromised. Similar stage-specific defects existed for erythroid progenitors from Kit Y567F/Y567F:Y569F/Y569F but not KIT Y719F/Y719F mice. Kit Y567F/Y567F erythroblasts were used further to analyze KIT-PY567–dependent signals. MEK-1,2/ERK-1,2 signaling was unaffected while AKT, p70S6K, and especially JNK2/p54 pathways were selectively attenuated. Conclusions Nonredundant KIT-PY567–directed erythroblast-intrinsic signals are selectively critical for stress erythropoiesis. Investigations also add to an understanding of how KIT directs distinct outcomes among diverse progenitors and lineages. |
| Databáze: | OpenAIRE |
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