Actin Cytoskeleton and Regulation of TGFβ Signaling: Exploring Their Links

Abstract

Human tissues, to maintain their architecture and function, respond to injuries by activating intricate biochemical and physical mechanisms that regulates intercellular communication crucial in maintaining tissue homeostasis. Coordination of the communication occurs through the activity of different actin cytoskeletal regulators, physically connected to extracellular matrix through integrins, generating a platform of biochemical and biomechanical signaling that is deregulated in cancer. Among the major pathways, a controller of cellular functions is the cytokine transforming growth factor β (TGFβ), which remains a complex and central signaling network still to be interpreted and explained in cancer progression. Here, we discuss the link between actin dynamics and TGFβ signaling with the aim of exploring their aberrant interaction in cancer.

Keywords: TGFβ; actin cytoskeleton; actin-binding proteins; extracellular matrix; tumor microenvironment.

Figure 1

Schematic representation of transforming growth factor β (TGFβ) signaling regulation by actin remodeling induced by extracellular matrix (ECM) stiffness. Activation of Rho GTPase by mechanical cues promotes F-actin assembly and actin cytoskeleton contractility, which activates TGFβ signaling by: (a) Inducing TGFβ ligand release and activation. The ECM-integrin-actin cytoskeleton linkages allow integrin to shift toward an active configuration that favors TGFβ release from LTBP/latent TGFβ complex. Active TGFβ initiates signaling via TGFβ receptors, which ultimately drives the phosphorylation-dependent formation of SMAD2/3-4 complex. This complex translocates to the nucleus and facilitates the transcription of TGFβ-dependent genes; (b) Accumulating at the front of the nucleus of the lamin-binding protein Nesprin-2, which induces SMAD nuclear localization; (c) Inhibiting the formation of both cytosolic and nuclear LEMD3-SMAD2/3 complexes, resulting in the relief of LEMD3 negative regulation; (d) Activating YAP/TAZ pathway, which regulates both SMAD2/3 shuttling and SMAD-dependent transcriptional activity; (e) Controlling myocardin-related transcription factor A (MRTF-A) localization to mediate the SMAD-dependent transcriptional activity.

Figure 2

Actin regulatory proteins controlling TGFβ type I receptors (TβRI) and II trafficking. (a) The internalized TβRI into clathrin-coated vesicles is linked to the actin cytoskeleton via fascin actin-bundling protein 1 (FSCN1) which promotes the trafficking of internalized receptors from clathrin-coated vesicles to early endosomes and thus TGFβ signaling. (b) VASP promotes TGFβ activity by sustaining the complex between Rab11 and TβRII that favors TβRII recycling to the plasma membrane. (c) Myosins sustain TGFβ signaling by sustaining the cell-surface expression of TβRII receptor and inhibiting its degradation. (d) Arf GAP with GTP-binding protein-like domain, Ankyrin repeat, and PH domain 2 isoform 2 (AGAP2) sustains TGFβ signaling, by directly or indirectly interacting with TβRII and sustaining the recycling of the receptor to the plasma membrane.

Figure 3

Actin cytoskeleton dynamics control the expression levels of Ski and SnoN, negative regulators of TGFβ signaling. TGFβ signaling controls expression levels of the negative regulators Ski and SnoN, by inducing both their upregulation and their ubiquitin (Ub)-mediated degradation. In normal hepatocytes, actin cytoskeleton dynamics induce Ski protein degradation and SnoN protein stabilization, and might impact TGFβ signaling outcome. This mechanism is lost in hepatoma cells [151,152].