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MECHANOTRANSDUCTION

HOW CELLS AND MATRIX WHISPER TO EACH OTHER

The ECM is a three-dimensional, structure that provides regulatory cues that are essential for maintaining the homeostasis of matrix proteins  and cell signaling mechanisms. Mechanical forces are basic stimuli that drive matrix remodeling and cells utilize mechanosensors that localize to cell-matrix adhesions, to check the state of the mechanical properties of the matrix. Indeed, cells perceive microenvironmental physical forces that are generated in ECM;  these forces are able to activate biochemical pathways that can modulate cell behaviors, such as cell proliferation, migration, and differentiation. The process, of the conversion of biophysical forces into biochemical signals to elicit cell responses is termed mechanotransduction. For this aim, exist specific plasma membrane receptors, that sense and trigger signaling cascades that generate and regulate biological functions. The cells and the matrix can dialogue and tune in to each other, in a functionally organized society, which it presides over basic molecular functions. Besides the membrane-associated receptors, mechanical forces can be directly transmitted to the nucleus that responds modifying transport of transcription factors and other nucleus-cytoplasm shuttling proteins, as well as redefine nucleoskeleton, detrmining cells fate and matrix remodelling.

INTEGRINS

Integrins are proteins that act mechanically, by sensing whether adhesion has occurred, attaching the cell cytoskeleton to the extracellular matrix (ECM). Integrins work as adhesion receptors for extracellular ligand fibronectin and transduce biochemical signals into the cell, through downstream effector proteins. They function bidirectionally, and they can transmit information both outside-in and inside-out. 

FIBRONECTIN (FBN)

Fibronectin is a cell-adhesive ECM protein, synthetized by fibroblasts to be then assembled into the ECM. FBN through binding integrin receptors of the cell surface, acts as a pivot player of the communication between the intra and the extracellular environment, and thus can control the cell behavior.

FIBRONECTIN–INTEGRIN RECOGNITION

Integrin is the main cell surface receptor that mediates cell-matrix adhesion, through fibronectin binding. Integrin consists of a extracellular domain with selectivity for ECM ligand fibronectin, a transmembrane domain and a short cytoplasmic tail. Integrin is structured to engage intracellular signaling molecules to reorganises the cytoskeletal networks and triggers a multiple signalling pathways that can cause changes in cell cycle, proliferation, differentiation, survival and motility.

CYTOSKELETON

Cytoskeleton is a dynamic structure present in the cytoplasm of cells and consists of three major types of filaments make up the cytoskeleton: actin filaments, microtubules  and intermediate filaments. Cytoskeleton give the cell its shape, provides a basis for movement and cell division. It is a meshworks through which mechanical stimuli, coming from the microenvironment of the matrix, can propagate and activate specific effector responses.

CALCIUM CHANNELS

Mechanical forces or any molecular event affecting the cell membrane, such as a growth factor, hormone, neurotransmitter or electromagnetic energy, emitted by the vibrations of these molecules, generates a huge release of calcium ions, that triggers a cascade mechanism of intracellular signals regulating important biological processes. Transient receptor potential vanilloid type 4 (TRPV4) is a mechanosensitive Ca2+-permeable channel that, when expressed in cell-matrix adhesions of the plasma membrane, regulates extracellular matrix (ECM) remodeling and cellular vital functions. 

G-PROTEIN COUPLED RECEPTORS

G-protein coupled receptors (GPCRs) are a family of 7-transmembrane-domain receptors. Mechanical stimuli causes activation of GPCRs and the downstream signaling pathways associated that finally results in a change in cell function.

 

 

 

MECHANICAL SIGNALING VIA YAP/TAZ

The transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two of the regulatory proteins of the "Hippo" signaling pathway which in turn plays a key role in cell proliferation and regeneration. YAP/TAZ plays a central role in mechano-transduction, responding to mechanical signals generated by the elasticity or rigidity of the extracellular matrix and providing these informations to the transcriptional structure of the nucleus. YAP/TAZ signaling pathway can be modulated by the physical properties of  ECM microenvironments. For example, stiff matrices leads to YAP/TAZ activation and their translocation into the nucleus. Conversely, soft matrix will result in inactivate YAP/TAZ, leading to their cytoplasmic retention. Thus,depending on its location (in the nucleus or in the cytoplasm), YAP/TAZ is able or not trigger the transcription of the genes responsible for cell division and apoptosis. The intra-nuclear localization of YAP (and therefore its activate form) is regulated, by the mechanical properties of the extracellular matrix. When cells are located in a soft matrix, the levels of cytoplasmic YAP/TAZ increase, and the rate of cell proliferation decreases. Conversely, when cells are in a rigid ECM environment, the cytoplasmic YAP/TAZ protein moves into the nucleus and induces cell proliferation. 

 

 

SIGNAL INTEGRATION BETWEEN THE TGF-β AND YAP/TAZ PATHWAYS IN ECM REMODELING.

TGF-β superfamily of growth factors consists of multiple  cytokine involved in many cellular processes, including stem cell pluripotency, cell fate determination, cell growth, apoptosis and homeostasis. TGF-β is stored in ECM in the so-called large latent complex (LLC). Disregulation of ECM turnover or increased mechanical forces cause release of TGF-β from the LLC allowing it to engage its receptors. Subsequently, the activated receptor is now able to bind and phosphorylate Smad proteins, that are intracellular signaling molecole. Smad complexes shuttle to the nucleus where they act to regulate transcription of target genes. TGF-β/Smad pathway is recognized as a primary regulator of extracellular matrix (ECM) homeostasis. TGF-β signaling is often perturbed in aged human skin due to reduced expression of TGF-β receptor and Smad activation. Impaired TGF-β signaling negatively regulates collagen homeostasis and has a significant impact on human skin connective tissue aging. As such, aberrant TGF-β signaling is closely linked to the pathophysiology of broad human diseases. YAP/TAZ modulates TGF-β/Smad pathway through a specific mechanism in human skin fibroblasts. Low levels of YAP/TAZ or inhibition of YAP/TAZ nuclear translocation lead to up-regulation of Smad7 expression, a Smad inhibitory protein. Elevated Smad7, in turn, inhibits Smad phosphorylation and impairs TGF-β/Smad pathway. These data support that YAP/TAZ works as an endogenous repressor of Smad7 expression to modulate TGF-β signaling.