title: SPREDs (Sprouty related proteins with EVH1 domain) promote self-renewal and inhibit mesodermal differentiation in murine embryonic stem cells.
abstract: BACKGROUND
  Pluripotency, self-renewal, and differentiation are special features of embryonic stem (ES) cells, thereby providing valuable perspectives in regenerative medicine. Developmental processes require a fine-tuned organization, mainly regulated by the well-known JAK/STAT, PI3K/AKT, and ERK/MAPK pathways. SPREDs (Sprouty related proteins with EVH1 domain) were discovered as inhibitors of the ERK/MAPK signaling pathway, whereas nothing was known about their functions in ES cells and during early differentiation, so far.
  
  
  RESULTS
  We generated SPRED1 and SPRED2 overexpressing and SPRED2 knockout murine ES cells to analyze the functions of SPRED proteins in ES cells and during early differentiation. Overexpression of SPREDs increases significantly the self-renewal and clonogenicity of murine ES cells, whereas lack of SPRED2 reduces proliferation and increases apoptosis. During early differentiation in embryoid bodies, SPREDs promote the pluripotent state and inhibit differentiation whereby mesodermal differentiation into cardiomyocytes is considerably delayed and inhibited. LIF- and growth factor-stimulation revealed that SPREDs inhibit ERK/MAPK activation in murine ES cells. However, no effects were detectable on LIF-induced activation of the JAK/STAT3, or PI3K/AKT signaling pathway by SPRED proteins.
  
  
  CONCLUSIONS
  We show that SPREDs promote self-renewal and inhibit mesodermal differentiation of murine ES cells by selective suppression of the ERK/MAPK signaling pathway in pluripotent cells.
authors.affiliation: Institute for Biochemistry and Molecular Biology, Ulm University, Ulm, Germany; Laboratory for Human Genetics, Martinsried, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Mühl
authors.forename: Jasmin
authors.initials: J
authors.lastname: Hägele
authors.forename: Alpaslan
authors.initials: A
authors.lastname: Tasdogan
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Loula
authors.forename: Kai
authors.initials: K
authors.lastname: Schuh
authors.forename: Karin
authors.initials: K
authors.lastname: Bundschu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D053605:Leukemia Inhibitory Factor / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D048049:Extracellular Signal-Regulated MAP Kinases; D053605:Leukemia Inhibitory Factor; D019869:Phosphatidylinositol 3-Kinases; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C507838:Lif protein, mouse; C433763:Spred1 protein, mouse; C433764:Spred2 protein, mouse; C494087:Stat3 protein, mouse
keywords: ERK/MAPK signaling; LIF; SPRED; STAT3; pluripotency