Mechanical regulation of the Notch signaling pathway.

The mechanical regulation of Notch signaling is an emerging area of interest in cell biology. Notch is essential in many physiological processes in which mechanical stress plays an important role. This review provides an overview of the mechanoregulation of Notch signaling in multiple steps of the pathway. First, we discuss the current knowledge on the direct mechanoregulation of Notch receptor maturation and localization to the membrane and the effect of mechanical stress on the Notch components. Next, we explore how ligand-receptor interactions and membrane dynamics are possible subjects to mechano-regulation, emphasizing the role of cytoskeletal interactions, membrane stiffness, and endocytic complex formation. We further delve into the necessity of tension generation for negative regulatory region (NRR) domain unfolding, facilitated by ligand endocytosis and other microforces. Additionally, we examine the indirect mechano-regulation of S2 and S3 cleavages. Finally, we discuss the mechanoregulation of the Notch intracellular domain (NICD) trafficking and nuclear entry and the impact of mechanical stress on heterochromatin dynamics and nuclear NICD interactions. This review aims to draw attention to the intricate interplay between mechanical cues and Notch signaling regulation, offering novel insights into the multifaceted nature of cellular mechanobiology.

From structural resilience to cell specification - Intermediate filaments as regulators of cell fate.

During the last decades intermediate filaments (IFs) have emerged as important regulators of cellular signaling events, ascribing IFs with functions beyond the structural support they provide. The organ and developmental stage-specific expression of IFs regulate cell differentiation within developing or remodeling tissues. Lack of IFs causes perturbed stem cell differentiation in vasculature, intestine, nervous system, and mammary gland, in transgenic mouse models. The aberrant cell fate decisions are caused by deregulation of different stem cell signaling pathways, such as Notch, Wnt, YAP/TAZ, and TGFß. Mutations in genes coding for IFs cause an array of different diseases, many related to stem cell dysfunction, but the molecular mechanisms remain unresolved. Here, we provide a comprehensive overview of how IFs interact with and regulate the activity, localization and function of different signaling proteins in stem cells, and how the assembly state and PTM profile of IFs may affect these processes. Identifying when, where and how IFs and cell signaling congregate, will expand our understanding of IF-linked stem cell dysfunction during development and disease.

Vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic stress.

The intermediate filament (IF) cytoskeleton has been proposed to regulate morphogenic processes by integrating the cell fate signaling machinery with mechanical cues. Signaling between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) through the Notch pathway regulates arterial remodeling in response to changes in blood flow. Here we show that the IF-protein vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic forces. Vimentin is important for Notch transactivation by ECs and vimentin knockout mice (VimKO) display disrupted VSMC differentiation and adverse remodeling in aortic explants and in vivo. Shear stress increases Jagged1 levels and Notch activation in a vimentin-dependent manner. Shear stress induces phosphorylation of vimentin at serine 38 and phosphorylated vimentin interacts with Jagged1 and increases Notch activation potential. Reduced Jagged1-Notch transactivation strength disrupts lateral signal induction through the arterial wall leading to adverse remodeling. Taken together we demonstrate that vimentin forms a central part of a mechanochemical transduction pathway that regulates multilayer communication and structural homeostasis of the arterial wall.