The extracellular matrix as a key regulator of intracellular signalling networks

Abstract

The extracellular matrix (ECM) is a salient feature of all solid tissues within the body. This complex, acellular entity is composed of hundreds of individual molecules whose assembly, architecture and biomechanical properties are critical to controlling the behaviour and phenotype of the different cell types residing within tissues. Cells are the basic unit of life and the core building block of tissues and organs. At their simplest, they follow a set of rules, governed by their genetic code and effected through the complex protein signalling networks that these genes encode. These signalling networks assimilate and process the information received by the cell to control cellular decisions that govern cell fate. The ECM is the biggest provider of external stimuli to cells and as such is responsible for influencing intracellular signalling dynamics. In this review, we discuss the inclusion of ECM as a central regulatory signalling sub-network in computational models of cellular decision making, with a focus on its role in diseases such as cancer. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc.

Figure 1

The effect of changes in ECM‐mediated signalling pathways. (A) Integrin activation by ECM components such as collagen, fibronectin, tenascin and laminin can phosphorylate the FAK/Src pathway and lead to downstream changes in cell adhesion and migration. Integrin‐mediated FAK/Src activation is also central to the activation of (B) MAPK signalling via ERK1/2 and JNK phosphorylation as well as (C) PI3K/Akt activation, leading to increased proliferation and cell survival through changes in transcriptional gene regulation. (D) FAK/Src activation can also mediate Rho/Rho‐associated kinase (ROCK) signalling, which affects cytoskeletal organization and cell motility in normal and diseased tissue states. (E) Fibrillar collagen in the ECM activates DDR2, which can mediate the MAPK and PI3K/Akt signalling pathways to influence gene expression and subsequently cellular behaviour. (F) Elastin binding to its receptor elastin binding protein receptor can influence PI3K/Akt signalling and MAPK signalling via ERK1/2. (G) Hyaluronan, another component of ECM remodelling, activates CD44 receptor, which can also affect Rho‐ROCK signalling.

Figure 2

Computational model of the interplay between the ECM and drug activated MAPK‐JNK signalling network (A) Scheme outlining how the ECM induced activation of ERK and PI3K/Akt influences the JNK signalling network. Black arrows represent activating biochemical reactions, red arrows represent inhibitory reactions. * and ** represents single and double phosphorylation events respectively on kinases. Red text represents model species in the inhibited state (also denoted by i ). (B) Simulated input/output curves showing the relationship between ECM stiffness and the basal state of both DUSP (dual‐specificity phosphatase) expression and the inhibited forms of ASK/MLK (apoptosis signal regulating kinase / mixed lineage kinase) and MKK4/7. (C) Simulated input/output curves showing the changes in ultrasensitivity of drug induced JNK activation as ECM stiffness is increased.