Tuning cell migration: contractility as an integrator of intracellular signals from multiple cues

Abstract

There has been immense progress in our understanding of the factors driving cell migration in both two-dimensional and three-dimensional microenvironments over the years. However, it is becoming increasingly evident that even though most cells share many of the same signaling molecules, they rarely respond in the same way to migration cues. To add to the complexity, cells are generally exposed to multiple cues simultaneously, in the form of growth factors and/or physical cues from the matrix. Understanding the mechanisms that modulate the intracellular signals triggered by multiple cues remains a challenge. Here, we will focus on the molecular mechanism involved in modulating cell migration, with a specific focus on how cell contractility can mediate the crosstalk between signaling initiated at cell-matrix adhesions and growth factor receptors.

Keywords: Contractility; Crosstalk; cell migration; focal adhesions.

Figure 1.. Matrix stiffness-mediated regulation of growth factor activation as a modulator of cell migration.

( A) Matrix stiffness regulates the formation of actin and cortactin-rich circular dorsal ruffle structures downstream of platelet-derived growth factor (PDGF) receptor activation in response to PDGF stimulation in smooth muscle cells (low stiffness: 1 kPa; high stiffness: 30 kPa; see for details). Scale bar is 20 μm. ( B) Schematics of proposed signaling crosstalk between focal adhesion (FA) and growth factor receptors depicting how increased matrix stiffness could potentiate growth factor-induced signaling, resulting in increased cell migration.

Figure 2.. Focal adhesion (FA) signaling nodes and their potential role in modulating response to growth factors and subsequent cell migration.

Schematics showing how the expression of different forms of mechanoregulating and scaffolding proteins in three cell types can influence intracellular signal integration by altering signaling nodes. Differential expression of these factors can alter the contractile state of the cell or directly enhance the feedback between growth factor receptors and FAs, resulting in a modulated response to growth factor stimulation that could regulate migration. These mechanoregulators can be structural and scaffolding proteins, such as different intermediate filaments (IFs), or signaling kinases, such as protein kinase C, or both. ECM, extracellular matrix.