Linking cell structure to gene regulation: Signaling events and expression controls on the model genes PAI-1 and CTGF

doi:10.1016/j.cellsig.2010.03.020

Cellular Signalling

Volume 22, Issue 10, October 2010, Pages 1413-1419

https://doi.org/10.1016/j.cellsig.2010.03.020 Get rights and content

Abstract

The microtubule and microfilament cytoskeletal systems as well as cell-to-cell contacts and cell–matrix interactions are critical regulators of cell structure and function. Alterations in cell shape profoundly influence signaling events and gene expression programs that impact a spectrum of biological responses including cell growth, migration and apoptosis. These same pathways also contribute to the progression of several important pathologic conditions (e.g., arteriosclerosis, vascular fibrosis, and endothelial dysfunction). Indeed, hemodynamic forces in the vascular compartment are established modifiers of endothelial and smooth muscle cell cytoarchitecture and orchestrate complex genetic and biological responses in concert with contributions from the extracellular matrix (ECM), growth factors (e.g., EGF, and TGF-β) and cell adhesion receptors (e.g., integrins, and cadherins). The profibrotic matricellular proteins plasminogen activator inhibitor-1 (PAI-1) and connective tissue growth factor (CTGF) are prominent members of a subset of genes the expression of which is highly responsive to cell shape-altering stimuli (i.e., disruption of the actin-based and microtubule networks, shear strain and cyclic stretch). Since both PAI-1 and CTGF are major mediators of cardiovascular fibrotic disease, understanding cell structure-linked signaling cascades provides potential avenues for focused therapy. It is increasingly evident that growth factor receptors (EGFR) are activated by changes in cytoarchitecture and that the “repressive state” of certain signaling proteins (e.g., SMAD, and Rho-GEFs) is maintained by sequestration on cell structural networks. Functional repression can be relieved by cytoskeletal perturbations (e.g., in response to treatment with network-specific drugs) resulting in activation of signaling cascades (e.g., Rho, and MAPK) with associated changes in gene reprogramming. Recent studies document a complex network of both similar and unique signaling control elements leading to the induction of PAI-1 and CTGF in response to modifications in cell shape. The purpose of this review is to highlight our current understanding of “cell deformation”-responsive signaling cascades focusing on the potential value of targeting such pathways, and their model response genes (e.g., PAI-1, and CTGF), as a therapeutic option for the treatment of fibrotic diseases.

Introduction

External physical forces as well as internal constraints imposed by the microtubule, microfilament and intermediate filament cytoskeletal networks, junctional complexes and integrin–extracellular matrix (ECM) interactions are major determinants of cell structure and function [e.g., [1], [2], [3]]. Indeed, several basic processes including cell cycle transit, DNA synthesis and apoptosis are profoundly influenced by changes in cellular structural organization [4], [5], [6], [7], [8], [9]. The vasculature, for example, is constantly subjected to a continuum of hemodynamic stimuli (e.g., shear strain, flow disturbances, mechanical or pulsile stretch) that alter cytoskeletal dynamics, organization and associated signaling pathways. These same mechanical forces impact expression of genes that, in turn, modulate cell proliferation, migration and ECM synthesis/deposition resulting in the development of tissue-specific pathologies (e.g., focal atherosclerosis) [reviewed in [10], [11], [12], [13], [14]]. Prominent among the repertoire of fibrosis-promoting proteins implicated in vascular fibroproliferative disease are the matricellular proteins plasminogen activator inhibitor inhibitor-1 (PAI-1, SERPINE1) and connective tissue growth factor (CTGF) [reviewed in [15], [16]]. Importantly, the transcriptional control networks for both genes are exquisitely sensitive to cytoskeletal perturbations [16]. The continued definition of pathways and mechanisms involved in vascular cell shape deformation responses may well define new, translationally-relevant, targets for the treatment of vascular disorders.

Section snippets

Mechanosensitive signaling: the vascular model

The available evidence suggests that, upon appropriate mechanical stimuli, integrins are mobilized to orchestrate cellular responses in coordination with (a) growth factor receptors (e.g., those that bind epidermal growth factor [EGFR], transforming growth factor-β [TGF-βR], vascular endothelial growth factor [VEGFR] family ligands), (b) cadherin junctional complexes and (c) clues from the ECM [10], [17], [18], [19], [20], [21]. Integrins, in fact, are focal points for recruitment of signaling

Cell shape-dependent metabolic controls: genomic responses to cytoskeletal deformation

Experimental approaches that specifically perturb cell structure (e.g., multidirectional force application, cadherin- or integrin-interfering antibodies, cytoskeletal-active drugs, expression of mutant or cell type “unrelated” cytoskeletal elements, substrate-modulation of cell morphology by plating on poly-HEMA-coated surfaces or on complex micro-patterned adhesive substrates) provide accessible models to probe deformation-sensitive signaling pathways and their target genes [e.g., [2], [3],

Transactivation of growth factor receptors and downstream signaling in response to cytoskeletal deformation

EGFR activation and engagement of downstream MAP kinases (e.g., ERK1/2) is a common response to microtubule destabilizing drugs resulting in specific changes in gene expression [16], [60], [61], [64], [77], [93], [94] (Fig. 2). EGFR phosphorylation upon microtubule disruption requires generation of reactive oxygen species (ROS) [e.g., 16], in sharp contrast to EGFR activation by native ligands [reviewed in 95]. Vascular cell shape perturbation by cytoskeletal deformation, moreover, involves

Molecular mechanisms of gene control in response to cell shape perturbation

While there is ample evidence that members of the Rho family impact gene expression, the underlying molecular mechanisms, particularly those involving interplay with cellular structural elements, are only partially understood. The linkage between cytoskeletal remodeling and gene regulation, moreover, largely focus on RhoA signaling and its downstream effectors ROCK and mDia leading to increases in cellular F-actin structures and a corresponding decrease in monomeric actin. Monomeric or G-actin

Summary and significance

Mechanosensory signaling pathways play a crucial role in vascular cell migration, proliferation and differentiation as well as disease progression [10], [13], [14], [21]. The “tensegrity model”, for example, suggests that the plasma membrane is hardwired to the nucleus via cytoskeletal networks facilitating signal propagation in response to mechanical stimuli originating from either ECM modifications or changes in tensional forces due to alterations of blood flow [reviewed in [8], [14]]. Recent

Acknowledgements

This work is supported by NIH grant GM57242.

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ReviewLinking cell structure to gene regulation: Signaling events and expression controls on the model genes PAI-1 and CTGF

Abstract

Introduction

Section snippets

Mechanosensitive signaling: the vascular model

Cell shape-dependent metabolic controls: genomic responses to cytoskeletal deformation

Transactivation of growth factor receptors and downstream signaling in response to cytoskeletal deformation

Molecular mechanisms of gene control in response to cell shape perturbation

Summary and significance

Acknowledgements

Biochem. Biophys. Res. Commun.

Cell

Cell

Biochem. Biophys. Res. Commun.

Curr. Opin. Cell Biol.

J. Biomech.

Dev. Cell.

Cell Signal

Biochim. Biophys. Acta

J. Biomech.

Cell

J. Biol. Chem.

J. Biol. Chem.

Microvasc. Res.

Curr. Biol.

J. Biol. Chem.

Exp. Cell Res.

J. Invest. Dermatol.

J. Biol. Chem.

Am. J. Path.

Biophys. J.

Biochem. Pharmacol.

J. Biol. Chem.

Curr. Opin. Cell Biol.

J. Biol. Chem.

J. Biol. Chem.

J. Invest. Dermatol.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Atherosclerosis

J. Biol. Chem.

Blood

Atherosclerosis

J. Biol. Chem.

Mol. Cell

J. Biol. Chem.

Exp. Cell Res.

J. Biol. Chem.

Cell Signal.

J. Biol. Chem.

J. Biol. Chem.

Kidney Int.

J. Biol. Chem.

Genes Dev.

J. Cell Sci.

Nature

Nat. Rev. Mol. Cell Biol.

J. Int. Med.

Am. J. Physiol. Heart Circ. Physiol.

Circ. Res.

Review
Linking cell structure to gene regulation: Signaling events and expression controls on the model genes PAI-1 and CTGF