Size-dependent protein segregation creates a spatial switch for Notch and APP signaling

Aberrant cleavage of Notch and amyloid precursor proteins (APPs) by γ-secretase is implicated in numerous diseases, but how cleavage is regulated in space and time is unclear. Here, we report that cadherin-based adherens junctions (cadAJs) are sites of high cell-surface γ-secretase activity, while simultaneously excluding these γ-secretase substrates by a size-dependent mechanism, prohibiting enzyme-substrate interactions. Upon activation, Notch and APP undergo drastic spatial rearrangements to cadAJs, concentrating them with γ-secretase, wherein they are further processed for downstream signaling. Spatial mutation by decreasing (or increasing) the size of Notch extracellular domain promotes (or inhibits) signaling, respectively. Dysregulation of this spatial switch also promotes formation of more amyloidogenic Aβ. Therefore, cadAJs creates distinct biochemical compartments regulating signaling events involving γ-secretase and prevent pathogenic activation of its substrates.

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Small Interfering RNAs Induce Macrophage Migration Inhibitory Factor Production and Proliferation in Breast Cancer Cells via a Double-Stranded RNA-Dependent Protein Kinase-Dependent Mechanism

The Journal of Immunology ◽

10.4049/jimmunol.180.11.7125 ◽

2008 ◽

Vol 180 (11) ◽

pp. 7125-7133 ◽

Cited By ~ 24

Author(s):

Michelle E. Armstrong ◽

Michael Gantier ◽

Lili Li ◽

Wen Y. Chung ◽

Amanda McCann ◽

...

Keyword(s):

Breast Cancer ◽

Protein Kinase ◽

Macrophage Migration Inhibitory Factor ◽

Breast Cancer Cells ◽

Macrophage Migration ◽

Small Interfering Rnas ◽

Dependent Protein Kinase ◽

Double Stranded Rna ◽

Dependent Protein ◽

Dependent Mechanism

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Altered Expression of Amyloid Precursor Proteins After Traumatic Brain Injury in Rats: In Situ Hybridization and Immunohistochemical Study

Journal of Neurotrauma ◽

10.1089/neu.2000.17.123 ◽

2000 ◽

Vol 17 (2) ◽

pp. 123-134 ◽

Cited By ~ 30

Author(s):

MAKOTO MASUMURA ◽

RYUJI HATA ◽

HIROSHI URAMOTO ◽

NORIHITO MURAYAMA ◽

TOMOCHIKA OHNO ◽

...

Keyword(s):

Traumatic Brain Injury ◽

In Situ Hybridization ◽

Brain Injury ◽

Immunohistochemical Study ◽

Amyloid Precursor Proteins ◽

Altered Expression ◽

Precursor Proteins

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Vav Family Proteins Couple to Diverse Cell Surface Receptors

Molecular and Cellular Biology ◽

10.1128/mcb.20.17.6364-6373.2000 ◽

2000 ◽

Vol 20 (17) ◽

pp. 6364-6373 ◽

Cited By ~ 106

Author(s):

Sheri L. Moores ◽

Laura M. Selfors ◽

Jessica Fredericks ◽

Timo Breit ◽

Keiko Fujikawa ◽

...

Keyword(s):

Growth Factor ◽

Cell Surface ◽

Tyrosine Phosphorylation ◽

Tyrosine Kinases ◽

Protein Tyrosine Kinase ◽

Receptor Activation ◽

Cell Surface Receptors ◽

Nucleotide Exchange ◽

Surface Receptors ◽

Downstream Signaling

ABSTRACT Vav proteins are guanine nucleotide exchange factors for Rho family GTPases which activate pathways leading to actin cytoskeletal rearrangements and transcriptional alterations. Vav proteins contain several protein binding domains which can link cell surface receptors to downstream signaling proteins. Vav1 is expressed exclusively in hematopoietic cells and tyrosine phosphorylated in response to activation of multiple cell surface receptors. However, it is not known whether the recently identified isoforms Vav2 and Vav3, which are broadly expressed, can couple with similar classes of receptors, nor is it known whether all Vav isoforms possess identical functional activities. We expressed Vav1, Vav2, and Vav3 at equivalent levels to directly compare the responses of the Vav proteins to receptor activation. Although each Vav isoform was tyrosine phosphorylated upon activation of representative receptor tyrosine kinases, integrin, and lymphocyte antigen receptors, we found unique aspects of Vav protein coupling in each receptor pathway. Each Vav protein coprecipitated with activated epidermal growth factor and platelet-derived growth factor (PDGF) receptors, and multiple phosphorylated tyrosine residues on the PDGF receptor were able to mediate Vav2 tyrosine phosphorylation. Integrin-induced tyrosine phosphorylation of Vav proteins was not detected in nonhematopoietic cells unless the protein tyrosine kinase Syk was also expressed, suggesting that integrin activation of Vav proteins may be restricted to cell types that express particular tyrosine kinases. In addition, we found that Vav1, but not Vav2 or Vav3, can efficiently cooperate with T-cell receptor signaling to enhance NFAT-dependent transcription, while Vav1 and Vav3, but not Vav2, can enhance NFκB-dependent transcription. Thus, although each Vav isoform can respond to similar cell surface receptors, there are isoform-specific differences in their activation of downstream signaling pathways.

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