Cytosolic interaction between deltex and Notch ankyrin repeats implicates deltex in the Notch signaling pathway

Development ◽  
1994 ◽  
Vol 120 (3) ◽  
pp. 473-481 ◽  
Author(s):  
R.J. Diederich ◽  
K. Matsuno ◽  
H. Hing ◽  
S. Artavanis-Tsakonas
Keyword(s):  
Notch Signaling ◽  
Cultured Cells ◽  
Direct Interaction ◽  
Notch Signaling Pathway ◽  
Wing Disc ◽  
The Novel ◽  
Ankyrin Repeats ◽  
New Class ◽  
Conserved Domain ◽  
Expression Studies

Genetic data from Drosophila have suggested a functional relationship between the novel cytoplasmic protein encoded by the deltex locus and the transmembrane receptor encoded by Notch. We have demonstrated a direct interaction between these proteins from expression studies conducted in cultured cells, in yeast, and in the imaginal wing disc. deltex binds specifically to the Notch ankyrin repeats, a region that is crucial for Notch signaling and that constitutes the most conserved domain among Notch family members. In addition, we present a new Notch allele, Nsu42c, that is associated with a missense mutation within the fifth ankyrin repeat. In addition to representing a new class of viable Notch allele, this mutation behaves similarly to mutations of deltex and further implicates the ankyrin repeats in Notch function.

Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats

Development ◽  
1995 ◽  
Vol 121 (8) ◽  
pp. 2633-2644 ◽  
Author(s):  
K. Matsuno ◽  
R.J. Diederich ◽  
M.J. Go ◽  
C.M. Blaumueller ◽  
S. Artavanis-Tsakonas
Keyword(s):  
Notch Signaling ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Ankyrin Repeats ◽  
Suppressor Of Hairless ◽  
Expression Studies ◽  
Heterotypic Interactions ◽  
Interaction Domains ◽  
Physical Interactions

We present a molecular and genetic analysis which elucidates the role of deltex in the Notch signaling pathway. Using the yeast ‘interaction trap’ assay, we define the protein regions responsible for heterotypic interactions between Deltex and the intracellular domain of Notch as well as uncover homotypic interaction among Deltex molecules. The function of the Deltex-Notch interaction domains is examined by in vivo expression studies. Taken together, data from overexpression of Deltex fragments and from studies of physical interactions between Deltex and Notch, suggest that Deltex positively regulates the Notch pathway through interactions with the Notch ankyrin repeats. Experiments involving cell cultures indicate that the Deltex-Notch interaction prevents the cytoplasmic retention of the Suppressor of Hairless protein, which otherwise is sequestered in the cytoplasm via association with the Notch ankyrin repeats and translocates to the nucleus when Notch binds to its ligand Delta. On the basis of these findings, we propose a model wherein Deltex regulates Notch activity by antagonizing the interaction between Notch and Suppressor of Hairless.

scholarly journals GPR50 Promotes Hepatocellular Carcinoma Progression via the Notch Signaling Pathway through Direct Interaction with ADAM17

2020 ◽  
Vol 17 ◽  
pp. 332-349 ◽  
Author(s):  
Subbroto Kumar Saha ◽  
Hye Yeon Choi ◽  
Gwang-Mo Yang ◽  
Polash Kumar Biswas ◽  
Kyeongseok Kim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Direct Interaction ◽  
Notch Signaling Pathway

scholarly journals The Role of Notch Signaling and Leptin-Notch Crosstalk in Pancreatic Cancer

Medicines ◽  
2018 ◽  
Vol 5 (3) ◽  
pp. 68 ◽  
Author(s):  
Adriana Harbuzariu ◽  
Gabriela Oprea-Ilies ◽  
Ruben Gonzalez-Perez
Keyword(s):  
Pancreatic Cancer ◽  
Notch Signaling ◽  
Cancer Progression ◽  
Treatment Success ◽  
Notch Signaling Pathway ◽  
Cancer Development ◽  
Cancer Cell Proliferation ◽  
The Novel ◽  
Cancer Types

There is accumulating evidence that deregulated Notch signaling affects cancer development, and specifically pancreatic cancer (PC) progression. Notch canonical and non-canonical signaling has diverse impact on PC. Moreover, the actions of RBP-Jk (nuclear partner of activated Notch) independent of Notch signaling pathway seem to affect differently cancer progression. Recent data show that in PC and other cancer types the adipokine leptin can modulate Notch/RBP-Jk signaling, thereby, linking the pandemic obesity with cancer and chemoresistance. The potential pivotal role of leptin on PC, and its connection with Notch signaling and chemoresistance are still not completely understood. In this review, we will describe the most important aspects of Notch-RBP-Jk signaling in PC. Further, we will discuss on studies related to RBP-Jk-independent Notch and Notch-independent RPB-Jk signaling. We will also discuss on the novel crosstalk between leptin and Notch in PC and its implications in chemoresistance. The effects of leptin-Notch/RBP-Jk signaling on cancer cell proliferation, apoptosis, and drug resistance require more investigation. Data from these investigations could help to open unexplored ways to improve PC treatment success that has shown little progress for many years.

scholarly journals Synergy between suppressor of Hairless and Notch in regulation of Enhancer of split m gamma and m delta expression.

1997 ◽  
Vol 17 (9) ◽  
pp. 5620-5628 ◽  
Author(s):  
D S Eastman ◽  
R Slee ◽  
E Skoufos ◽  
L Bangalore ◽  
S Bray ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Cell Fate ◽  
Transcriptional Activation ◽  
Cultured Cells ◽  
Notch Signaling Pathway ◽  
Cell Fate Decisions ◽  
Suppressor Of Hairless ◽  
Enhancer Of Split

The Notch signaling pathway is known to regulate cell fate decisions in a variety of organisms from worms to humans. Although several components of the pathway have been characterized, the actual mechanism and molecular results of signaling remain elusive. We have examined the role of the Notch signaling pathway in the transcriptional regulation of two Drosophila Enhancer of split [E(spl)] genes, whose gene products have been shown to be downstream players in the pathway. Using a reporter assay system in Drosophila tissue culture cells, we have observed a significant induction of E(spl) m gamma and m delta expression after cotransfection with activated Notch. Characterization of the 5' regulatory regions of these two genes led to the identification of a number of target sites for the Suppressor of Hairless [Su(H)] protein, a transcription factor activated by Notch signaling. We show that Notch-inducible expression of E(spl) m gamma and m delta both in cultured cells and in vivo is dependent on functional Su(H). Although overexpression of Su(H) augments the level of induction of the reporter genes by activated Notch, Su(H) alone is insufficient to produce high levels of transcriptional activation. Despite the synergy observed between activated Notch and Su(H), the former affects neither the nuclear localization nor the DNA binding activity of the latter.

scholarly journals The Abelson tyrosine kinase and the Nedd4-family ubiquitin ligase Suppressor of Deltex converge at the Notch PPxY motif to regulate endosomal trafficking and signaling

2020 ◽  
Author(s):  
Nicelio Sanchez-Luege ◽  
Julio Miranda-Alban ◽  
Xiao Sun ◽  
Fernando M. Valbuena ◽  
Benjamin S. Glick ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Notch Signaling ◽  
Ubiquitin Ligase ◽  
Cultured Cells ◽  
Genetic Interaction ◽  
Notch Signaling Pathway ◽  
Endosomal Trafficking ◽  
Transcriptional Responses ◽  
Surface Receptors ◽  
Signaling Dynamics

AbstractThe conserved Notch signaling pathway coordinates diverse cellular processes during animal development. Unlike most cell surface receptors that use a cytoplasmic cascade to amplify and diversify signaling dynamics, Notch itself transduces external cues directly to the nucleus. How appropriate signaling dynamics and transcriptional responses are achieved with this pathway architecture remains unclear. Here, we report that the cytoplasmic tyrosine kinase Abelson (Abl) fine-tunes Notch signaling by regulating Notch endocytic trafficking. We show that Abl can directly phosphorylate a PPxY motif important for Nedd4-family ubiquitin-ligase-mediated transfer of Notch into degradative endosomal compartments. Consistent with this, loss of Abl or inhibition of its kinase activity results in aberrant endosomal accumulation of Notch, while mutation of the PPxY tyrosine renders Notch insensitive to such regulation. Phenotypic and genetic interaction studies in the wing, together with parallel assays in cultured cells, show that loss or gain of Abl activity can respectively increase or decrease Notch output. We propose that the Notch PPxY motif operates as a molecular hub that integrates multiple post-translational modifications to regulate Notch trafficking and fine-tune signaling output.

Regulation of EMT by Notch Signaling Pathway in Tumor Progression

2013 ◽  
Vol 13 (9) ◽  
pp. 957-962 ◽  
Author(s):  
Yumei Li ◽  
Jia Ma ◽  
Xiujuan Qian ◽  
Qiong Wu ◽  
Jun Xia ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Signaling Pathway
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