TY  - JOUR
AU  - Waschbüsch, D.
AU  - Born, S.
AU  - Niediek, V.
AU  - Kirchgeßner, N.
AU  - Tamboli, I.Y.
AU  - Walter, J.
AU  - Merkel, R.
AU  - Hoffmann, B.
TI  - Presenilin 1 affects focal adhesion site formation and cell force generation via c-Src transcriptional and posttranslational regulation
JO  - The journal of biological chemistry
VL  - 284
SN  - 0021-9258
CY  - Bethesda, Md.
PB  - Soc.
M1  - PreJuSER-6381
PY  - 2009
N1  - 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.
AB  - 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.
KW  - Animals
KW  - Cell Line
KW  - Cytoplasm: metabolism
KW  - Ephrin-B2: metabolism
KW  - Fibroblasts: metabolism
KW  - Focal Adhesions
KW  - Gene Expression Regulation
KW  - Mice
KW  - Microscopy, Fluorescence
KW  - Models, Biological
KW  - Phenotype
KW  - Presenilin-1: metabolism
KW  - Protein Processing, Post-Translational
KW  - Tyrosine: chemistry
KW  - src-Family Kinases: metabolism
KW  - Ephrin-B2 (NLM Chemicals)
KW  - Presenilin-1 (NLM Chemicals)
KW  - Tyrosine (NLM Chemicals)
KW  - src-Family Kinases (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:19176482
C2  - pmc:PMC2665068
UR  - <Go to ISI:>//WOS:000264892900056
DO  - DOI:10.1074/jbc.M806825200
UR  - https://juser.fz-juelich.de/record/6381
ER  -