Extracellular matrix-induced transforming growth factor-β receptor signaling dynamics

Abstract

Matrix remodeling, degradation, inflammation and invasion liberate peptide fragments that can subsequently interact with cells in an attachment-independent manner. Such 'soluble' matrix components, including collagens, fibronectin and laminin, induced Smad activation (termed crosstalk signaling), which follows a similar chronological sequence and R-Smad specificity as induced by transforming growth factor (TGF)-b1. Smad4 nuclear translocation occurred in response to collagen binding, indicating downstream signal propagation. TGF-b scavenging antibody affected only TGF-b1, but not crosstalk-induced responses. TGF-b type II receptor mutation (DR26D25), which is deficient in TGF-b type I receptor recruitment to the ligand, induced a heterotetramer signaling complex, and propagated Smad2 activation only through collagen induction and not TGF-b signaling. Consequentially, TGF-b ligand participation is not required for crosstalk signaling. This signaling requires a functional integrin b1 receptor as showed by RNA interference. Co-immunoprecipitation (co-IP) and fluorescent microscopy indicate the involvement of focal adhesion kinase (FAK) and Src activity in collagen-induced signal propagation, and suggest a membrane signaling complex formation that includes both TGF-b receptors and integrins. The related gene expressional responses are distinct from that evoked by TGF-b1, supporting its separate function. This signaling mechanism expands and partially explains TGFb receptor dynamics and consequential signaling diversityrelated gene expressional plasticity.

The TGF-β/Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system

“…This suggests that cells produce TGF--like activity and stimulate invasion in an autocrine manner. This is in agreement with a recent report in which it is shown that the ECM can induce TGF-signaling in the absence of TGF- [48]. We cannot exclude that Our studies reveal a key role for MMP2 and MMP9 in TGF--induced invasion of the highly aggressive M4 spheroids.…”

Impaired cornea wound healing in a tenascin C-deficient mouse model

“…Activation of an integrin could initiate TGFb/Smad signaling via interaction with TGFb receptor. 31,32 TGFb-induced phenotypic changes were not observed in cells in suspension and were dependent on b1-33 or a3b1-integrin 34 . TGFb-mediated cellular transdifferentiation to a more fibrogenic phenotype, such as the myofibroblast or EMT, appears to require integrins.…”

The wound healing, chronic fibrosis, and cancer progression triad

“…To further fuel the recurring cycle, EMT enhances the expression of MMP-2 and MMP-9 (36). Interestingly, MMP cleaved ECM peptides (i.e., soluble ECMs) are known to induce an integrin-dependent TGF-␤-like signaling response (106). Also, CD147, a cell-surface glycoprotein upregulated in tumor cells, can stimulate both stromal MMP production and myofibroblast differentiation (147).…”