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

Oncogene. 2010 Apr 22;29(16):2368-80. doi: 10.1038/onc.2009.514. Epub 2010 Jan 25.


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)-beta1. Smad4 nuclear translocation occurred in response to collagen binding, indicating downstream signal propagation. TGF-beta scavenging antibody affected only TGF-beta1, but not crosstalk-induced responses. TGF-beta type II receptor mutation (DR26Delta25), which is deficient in TGF-beta type I receptor recruitment to the ligand, induced a heterotetramer signaling complex, and propagated Smad2 activation only through collagen induction and not TGF-beta signaling. Consequentially, TGF-beta ligand participation is not required for crosstalk signaling. This signaling requires a functional integrin beta1 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-beta receptors and integrins. The related gene expressional responses are distinct from that evoked by TGF-beta1, supporting its separate function. This signaling mechanism expands and partially explains TGF-beta receptor dynamics and consequential signaling diversity-related gene expressional plasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Collagen / pharmacology
  • Extracellular Matrix / physiology*
  • Humans
  • Integrin beta1 / physiology
  • Models, Biological
  • Phosphorylation
  • Receptor Cross-Talk / physiology
  • Receptors, Collagen / physiology
  • Receptors, Transforming Growth Factor beta / physiology*
  • Signal Transduction / physiology*
  • Smad Proteins / metabolism


  • Integrin beta1
  • Receptors, Collagen
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • Collagen