Extracellular matrix-induced transforming growth factor-beta receptor signaling dynamics.
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.
Garamszegi
N
N
Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA. ngaramszegi@med.miami.edu
Garamszegi
S P
SP
Samavarchi-Tehrani
P
P
Walford
E
E
Schneiderbauer
M M
MM
Wrana
J L
JL
Scully
S P
SP
D045744:Cell Line, Tumor; D003094:Collagen / Q000494:pharmacology; D005109:Extracellular Matrix / Q000502:physiology*; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology; D008954:Models, Biological; D010766:Phosphorylation; D020239:Receptor Cross-Talk / Q000502:physiology; D038981:Receptors, Collagen / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000378:metabolism
D019012:Integrin beta1; D038981:Receptors, Collagen; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D003094:Collagen