期刊
ONCOGENE
卷 29, 期 16, 页码 2368-2380出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2009.514
关键词
attachment-independent signaling; extracellular matrix; gene expressional plasticity; Smads; TGF-beta and integrin receptors
资金
- National Institutes of Health [CA-66088Y]
- American Cancer Society [ACS 66105H]
- Woman's Cancer Association [WCA 66461Y]
- University of Miami Orthopaedics Department
- Sylvester Comprehensive Cancer Center
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)-beta 1. Smad4 nuclear translocation occurred in response to collagen binding, indicating downstream signal propagation. TGF-beta scavenging antibody affected only TGF-beta 1, but not crosstalk-induced responses. TGF-beta type II receptor mutation (DR26 Delta 25), 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 beta 1 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-beta 1, supporting its separate function. This signaling mechanism expands and partially explains TGF-beta receptor dynamics and consequential signaling diversity-related gene expressional plasticity. Oncogene (2010) 29, 2368-2380; doi:10.1038/onc.2009.514; published online 25 January 2010
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