Interplay between ADP-ribosyltransferases and essential cell signaling pathways controls cellular responses

AbstractSignaling cascades provide integrative and interactive frameworks that allow the cell to respond to signals from its environment and/or from within the cell itself. The dynamic regulation of mammalian cell signaling pathways is often modulated by cascades of protein post-translational modifications (PTMs). ADP-ribosylation is a PTM that is catalyzed by ADP-ribosyltransferases and manifests as mono- (MARylation) or poly- (PARylation) ADP-ribosylation depending on the addition of one or multiple ADP-ribose units to protein substrates. ADP-ribosylation has recently emerged as an important cell regulator that impacts a plethora of cellular processes, including many intracellular signaling events. Here, we provide an overview of the interplay between the intracellular diphtheria toxin-like ADP-ribosyltransferase (ARTD) family members and five selected signaling pathways (including NF-κB, JAK/STAT, Wnt-β-catenin, MAPK, PI3K/AKT), which are frequently described to control or to be controlled by ADP-ribosyltransferases and how these interactions impact the cellular responses.

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Roles of mTOR in thoracic aortopathy understood by complex intracellular signaling interactions

PLoS Computational Biology ◽

10.1371/journal.pcbi.1009683 ◽

2021 ◽

Vol 17 (12) ◽

pp. e1009683

Author(s):

Ana C. Estrada ◽

Linda Irons ◽

Bruno V. Rego ◽

Guangxin Li ◽

George Tellides ◽

...

Keyword(s):

Smooth Muscle ◽

Cell Signaling ◽

Smooth Muscle Cell ◽

Signaling Pathways ◽

Muscle Cell ◽

Intracellular Signaling ◽

Cellular Mechanisms ◽

Data Set ◽

Bistable Switch ◽

Cell Signaling Pathways

Thoracic aortopathy–aneurysm, dissection, and rupture–is increasingly responsible for significant morbidity and mortality. Advances in medical genetics and imaging have improved diagnosis and thus enabled earlier prophylactic surgical intervention in many cases. There remains a pressing need, however, to understand better the underlying molecular and cellular mechanisms with the hope of finding robust pharmacotherapies. Diverse studies in patients and mouse models of aortopathy have revealed critical changes in multiple smooth muscle cell signaling pathways that associate with disease, yet integrating information across studies and models has remained challenging. We present a new quantitative network model that includes many of the key smooth muscle cell signaling pathways and validate the model using a detailed data set that focuses on hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and its inhibition using rapamycin. We show that the model can be parameterized to capture the primary experimental findings both qualitatively and quantitatively. We further show that simulating a population of cells by varying receptor reaction weights leads to distinct proteomic clusters within the population, and that these clusters emerge due to a bistable switch driven by positive feedback in the PI3K/AKT/mTOR signaling pathway.

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