Journal Article

PreJuSER-6381

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Presenilin 1 affects focal adhesion site formation and cell force generation via c-Src transcriptional and posttranslational regulation

Waschbüsch, D.FZJ* ; Born, S.FZJ* ; Niediek, V.FZJ* ; Kirchgeßner, N.FZJ* ; Tamboli, I. Y.FZJ* ; Walter, J.FZJ* ; Merkel, R.FZJ* ; Hoffmann, B.FZJ*

2009
Soc. Bethesda, Md.

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Please use a persistent id in citations: doi:10.1074/jbc.M806825200

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.

Keyword(s): Animals (MeSH) ; Cell Line (MeSH) ; Cytoplasm: metabolism (MeSH) ; Ephrin-B2: metabolism (MeSH) ; Fibroblasts: metabolism (MeSH) ; Focal Adhesions (MeSH) ; Gene Expression Regulation (MeSH) ; Mice (MeSH) ; Microscopy, Fluorescence (MeSH) ; Models, Biological (MeSH) ; Phenotype (MeSH) ; Presenilin-1: metabolism (MeSH) ; Protein Processing, Post-Translational (MeSH) ; Tyrosine: chemistry (MeSH) ; src-Family Kinases: metabolism (MeSH) ; Ephrin-B2 ; Presenilin-1 ; Tyrosine ; src-Family Kinases ; J

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.

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Contributing Institute(s):

1. Biomechanik (IBN-4)

Research Program(s):

1. Kondensierte Materie (P54)

Appears in the scientific report 2009

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