Article by Disease | Notch Signaling in Normal and Disease States: Possible Therapies Related to Glycosylation

 

Bentham Cardiovascular Disorders Collection | Alagille Syndrome

 

 

 

Abstract:

The Notch signaling pathway is involved in a wide variety of highly conserved developmental processes in mammals. Importantly, mutations of the Notch protein and components of its signaling pathway have been implicated in an array of human diseases (T-cell leukemia and other cancers, Multiple Sclerosis, CADASIL, Alagille Syndrome, Spondylocostal Dysostosis). In mammals, Notch becomes activated upon binding of its extracellular domain to ligands (Delta and Jagged/Serrate) that are present on the surface of apposed cells. The extracellular domain of Notch contains up to 36 tandem Epidermal Growth Factor-like (EGF) repeats. Many of these EGF repeats are modified at evolutionarily-conserved consensus sites by an unusual form of O-glycosylation called O-fucose. Work from several groups indicates that O-fucosylation plays an important role in ligand mediated Notch signaling. Recent evidence also suggests that the enzyme responsible for addition of O-fucose to Notch, protein O-fucosyltransferase-1 (POFUT1), may serve a quality control function in the endoplasmic reticulum. Additionally, some of the O-fucose moieties are further elongated by the action of members of the Fringe family of β-1,3-N-acetylglucosaminyltransferases. The alteration in O-fucose saccharide structure caused by Fringe modulates the response of Notch to its ligands. Thus, glycosylation serves an important role in regulating Notch activity. This review focuses on the role of glycosylation in the normal functioning of the Notch pathway. As well, potential roles for glycosylation in Notch-related human diseases, and possible roles for therapeutic targeting of POFUT1 and Fringe in Notch-related human diseases, are discussed.

 

Read out more at: http://www.eurekaselect.com/node/59354/article

Most Accessed Article – Warming Up to New Possibilities with the Capsaicin Receptor TRPV1: mTOR, AMPK, and Erythropoietin – Current Neurovascular Research

Journal: Current Neurovascular Research

Author(s): Kenneth Maiese.

Abstract:

Background: Transient receptor potential (TRP) channels are a superfamily of ion channels termed after the trp gene in Drosophila that are diverse in structure and control a wide range of biological functions including cell development and growth, thermal regulation, and vascular physiology. Of significant interest is the transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor, also known as the capsaicin receptor and the vanilloid receptor 1, that is a non-selective cation channel sensitive to a host of external stimuli including capsaicin and camphor, venoms, acid/basic pH changes, and temperature.

Methods: Given the multiple modalities that TRPV1 receptors impact in the body, we examined and discussed the role of these receptors in vasomotor control, metabolic disorders, cellular injury, oxidative stress, apoptosis, autophagy, and neurodegenerative disorders and their overlap with other signal transduction pathways that impact trophic factors.

Results: Surprisingly, TRPV1 receptors do not rely entirely upon calcium signaling to affect cellular biology, but also have a close relationship with the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and protein kinase B (Akt) that have roles in pain sensitivity, stem cell development, cellular survival, and cellular metabolism. These pathways with TRPV1 converge in the signaling of growth factors with recent work highlighting a relationship with erythropoietin (EPO). Angiogenesis and endothelial tube formation controlled by EPO requires, in part, the activation of TRPV1 receptors in conjunction with Akt and AMPK pathways.
Conclusion: TRPV1 receptors could prove to become vital to target disorders of vascular origin and neurodegeneration. Broader and currently unrealized implementations for both EPO and TRPV1 receptors can be envisioned for for the development of novel therapeutic strategies in multiple systems of the body.

 

To access the article, please visit: http://www.eurekaselect.com/150838

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