title: Genetic disruption of the scaffolding protein, Kinase Suppressor of Ras 1 (KSR1), differentially regulates GM-CSF-stimulated hyperproliferation in hematopoietic progenitors expressing activating PTPN11 mutants D61Y and E76K.
abstract: Activating PTPN11 mutants promote hematopoietic progenitor hyperactivation of Erk and hypersensitivity to GM-CSF. We hypothesized that Kinase Suppressor of Ras 1 (KSR1) contributes to activating PTPN11-induced GM-CSF hypersensitivity. Bone marrow progenitors from WT and KSR1-/- mice expressing WT Shp2, Shp2E76K, or Shp2D61Y were evaluated functionally and biochemically. KSR1 activation and interaction with phospho-Erk was enhanced in Shp2D61Y- and ShpE76K-expressing cells. Genetic disruption of KSR1 partially normalized Shp2E76K-induced GM-CSF hypersensitivity, but failed to correct Shp2D61Y-induced GM-CSF hypersensitivity. Collectively, these studies suggest that cells expressing Shp2E76K have a greater dependence on KSR1 for GM-CSF hypersensitivity than cells expressing Shp2D61Y.
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Zhenyun
authors.initials: Z
authors.lastname: Yang
authors.forename: Mia
authors.initials: M
authors.lastname: Chen
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Sitarski
authors.forename: Tirajeh
authors.initials: T
authors.lastname: Saadatzadeh
authors.forename: Fuqin
authors.initials: F
authors.lastname: Yin
authors.forename: Menggang
authors.initials: M
authors.lastname: Yu
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Chan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse