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@ARTICLE{Waschbsch:6381,
      author       = {Waschbüsch, D. and Born, S. and Niediek, V. and
                      Kirchgeßner, N. and Tamboli, I.Y. and Walter, J. and
                      Merkel, R. and Hoffmann, B.},
      title        = {{P}resenilin 1 affects focal adhesion site formation and
                      cell force generation via c-{S}rc transcriptional and
                      posttranslational regulation},
      journal      = {The journal of biological chemistry},
      volume       = {284},
      issn         = {0021-9258},
      address      = {Bethesda, Md.},
      publisher    = {Soc.},
      reportid     = {PreJuSER-6381},
      year         = {2009},
      note         = {This work was supported by Deutsche Forschungsgemeinschaft
                      Sonderforschungsbereich 645. The costs of publication of
                      this article were defrayed in part by the payment of page
                      charges. This article must therefore be hereby marked
                      "advertisement" in accordance with 18 U. S. C. Section 1734
                      solely to indicate this fact.},
      abstract     = {Presenilin 1 and 2 (PS) are critical components of the
                      gamma-secretase complex that cleaves type I transmembrane
                      proteins within their transmembrane domains. This process
                      leads to release of proteolytically processed products from
                      cellular membranes and plays an essential role in signal
                      transduction or vital functions as cell adhesion. Here we
                      studied the function of presenilins in cell-matrix
                      interaction of wild-type and PS knock-out mouse embryonic
                      fibroblasts. We found for PS1(-/-) cells an altered
                      morphology with significantly reduced sizes of focal
                      adhesion sites compared with wild type. Cell force analyses
                      on micropatterned elastomer films revealed PS1(-/-) cell
                      forces to be reduced by $50\%.$ Pharmacological inhibition
                      confirmed this function of gamma-secretase in adhesion site
                      and cell force formation. On the regulatory level, PS1
                      deficiency was associated with strongly decreased
                      phosphotyrosine levels of focal adhesion site-specific
                      proteins. The reduced tyrosine phosphorylation was caused by
                      a down-regulation of c-Src kinase activity primarily at the
                      level of c-Src transcription. The direct regulatory
                      connection between PS1 and c-Src could be identified with
                      ephrinB2 as PS1 target protein. Overexpression of ephrinB2
                      cytoplasmic domain resulted in its nuclear translocation
                      with increased levels of c-Src and a full complementation of
                      the PS1(-/-) adhesion and phosphorylation phenotype.
                      Cleavage of full-length EB2 and subsequent intracellular
                      domain translocation depended on PS1 as these processes were
                      only found in WT cells. Therefore, we conclude that
                      gamma-secretase is vital for controlling cell adhesion and
                      force formation by transcriptional regulation of c-Src via
                      ephrinB2 cleavage.},
      keywords     = {Animals / Cell Line / Cytoplasm: metabolism / Ephrin-B2:
                      metabolism / Fibroblasts: metabolism / Focal Adhesions /
                      Gene Expression Regulation / Mice / Microscopy, Fluorescence
                      / Models, Biological / Phenotype / Presenilin-1: metabolism
                      / Protein Processing, Post-Translational / Tyrosine:
                      chemistry / src-Family Kinases: metabolism / Ephrin-B2 (NLM
                      Chemicals) / Presenilin-1 (NLM Chemicals) / Tyrosine (NLM
                      Chemicals) / src-Family Kinases (NLM Chemicals) / J
                      (WoSType)},
      cin          = {IBN-4},
      ddc          = {570},
      cid          = {I:(DE-Juel1)VDB802},
      pnm          = {Kondensierte Materie},
      pid          = {G:(DE-Juel1)FUEK414},
      shelfmark    = {Biochemistry $\&$ Molecular Biology},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:19176482},
      pmc          = {pmc:PMC2665068},
      UT           = {WOS:000264892900056},
      doi          = {10.1074/jbc.M806825200},
      url          = {https://juser.fz-juelich.de/record/6381},
}