Dataset Information

Decoding the PTM-switchboard of Notch.

ABSTRACT: The developmentally indispensable Notch pathway exhibits a high grade of pleiotropism in its biological output. Emerging evidence supports the notion of post-translational modifications (PTMs) as a modus operandi controlling dynamic fine-tuning of Notch activity. Although, the intricacy of Notch post-translational regulation, as well as how these modifications lead to multiples of divergent Notch phenotypes is still largely unknown, numerous studies show a correlation between the site of modification and the output. These include glycosylation of the extracellular domain of Notch modulating ligand binding, and phosphorylation of the PEST domain controlling half-life of the intracellular domain of Notch. Furthermore, several reports show that multiple PTMs can act in concert, or compete for the same sites to drive opposite outputs. However, further investigation of the complex PTM crosstalk is required for a complete understanding of the PTM-mediated Notch switchboard. In this review, we aim to provide a consistent and up-to-date summary of the currently known PTMs acting on the Notch signaling pathway, their functions in different contexts, as well as explore their implications in physiology and disease. Furthermore, we give an overview of the present state of PTM research methodology, and allude to a future with PTM-targeted Notch therapeutics.

SUBMITTER: Antfolk D

PROVIDER: S-EPMC7116576 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Decoding the PTM-switchboard of Notch.

Antfolk Daniel D Antila Christian C Kemppainen Kati K Landor Sebastian K-J SK Sahlgren Cecilia C

Biochimica et biophysica acta. Molecular cell research 20190711 12

The developmentally indispensable Notch pathway exhibits a high grade of pleiotropism in its biological output. Emerging evidence supports the notion of post-translational modifications (PTMs) as a modus operandi controlling dynamic fine-tuning of Notch activity. Although, the intricacy of Notch post-translational regulation, as well as how these modifications lead to multiples of divergent Notch phenotypes is still largely unknown, numerous studies show a correlation between the site of modific ...[more]

PMID: 31301363

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Project description:The mammalian retina displays incomplete intrinsic regenerative capacities; therefore, retina degeneration is a major cause of irreversible blindness such as glaucoma, age-related macular degeneration and diabetic retinopathy. These diseases lead to the loss of retinal cells and serious vision loss in the late stage. Stem cell transplantation is a great promising novel treatment for these incurable retinal degenerative diseases and represents an exciting area of regenerative neurotherapy. Several suitable stem cell sources for transplantation including human embryonic stem cells, induced pluripotent stem cells and adult stem cells have been identified as promising target populations. However, the retina is an elegant neuronal complex composed of various types of cells with different functions. The replacement of these different types of cells by transplantation should be addressed separately. So far, retinal pigment epithelium transplantation has achieved the most advanced stage of clinical trials, while transplantation of retinal neurons such as retinal ganglion cells and photoreceptors has been mostly studied in pre-clinical animal models. In this review, we opine on the key problems that need to be addressed before stem cells transplantation, especially for replacing injured retinal ganglion cells, may be used practically for treatment. A key problem we have called the Switchboard Dilemma is a major block to have functional retinal ganglion cell replacement. We use the public switchboard telephone network as an example to illustrate different difficulties for replacing damaged components in the retina that allow for visual signaling. Retinal ganglion cell transplantation is confronted by significant hurdles, because retinal ganglion cells receive signals from different interneurons, integrate and send signals to the correct targets of the visual system, which functions similar to the switchboard in a telephone network - therefore the Switchboard Dilemma.

Dataset Information

Decoding the PTM-switchboard of Notch.

Publications

Decoding the PTM-switchboard of Notch.

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