MAGP2 controls Notch via interactions with RGD binding integrins: Identification of a novel ECM–integrin–Notch signaling axis

Canonical Notch signaling involves Notch receptor activation via interaction with cell surface bound Notch ligand. Recent findings also indicate that Notch signaling may be modulated by cross-talk with other signaling mechanisms. The ECM protein MAGP2 was previously shown to regulate Notch in a cell...

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Bibliographic Details
Published in:Experimental cell research 2016-02, Vol.341 (1), p.84-91
Main Authors: Deford, Peter, Brown, Kasey, Richards, Rae Lee, King, Aric, Newburn, Kristin, Westover, Katherine, Albig, Allan R.
Format: Article
Language:English
Subjects:
Cell signaling
Cellular biology
Contractile Proteins - metabolism
Extracellular matrix
Glycoproteins - metabolism
Humans
Integrin
Integrins - metabolism
Intercellular Signaling Peptides and Proteins
Matrix
Notch
Oligopeptides - metabolism
Proteins
Receptors, Notch - metabolism
Signal Transduction
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Summary:Canonical Notch signaling involves Notch receptor activation via interaction with cell surface bound Notch ligand. Recent findings also indicate that Notch signaling may be modulated by cross-talk with other signaling mechanisms. The ECM protein MAGP2 was previously shown to regulate Notch in a cell type dependent manner, although the molecular details of this interaction have not been dissected. Here, we report that MAGP2 cell type specific control of Notch is independent of individual Notch receptor-ligand combinations but dependent on interaction with RGD binding integrins. Overexpressed MAGP2 was found to suppress transcriptional activity from the Notch responsive Hes1 promoter activity in endothelial cells, while overexpression of a RGD→RGE MAGP2 mutant increased Notch signaling in the same cell type. This effect was not unique to MAGP2 since the RGD domain of the ECM protein EGFL7 was also found to be an important modulator of Hes1 promoter activity. Independently of MAGP2 or EGFL7, inhibition of RGD-binding integrins with soluble RGD peptides also increased accumulation of active N1ICD fragments and Notch responsive promoter activity independently of changes in Notch1, Jag1, or Dll4 expression. Finally, β1 or β3 integrin blocking antibodies also enhanced Notch signaling. Collectively, these results answer the question of how MAGP2 controls cell type dependent Notch signaling, but more importantly uncover a new mechanism to understand how extracellular matrices and cellular environments impact Notch signaling. •A novel signaling mechanism between integrins and Notch is proposed.•ECM molecules MAGP2 and EGFL7 control Notch via RGD binding integrins.•Integrin–Notch signaling allows Notch to responds to cellular microenvironment.•Integrin–Notch signaling helps explain pro- and anti-Notch activity of MAGP2.
ISSN:0014-4827
1090-2422
DOI:10.1016/j.yexcr.2016.01.011