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

Oncogene volume 29, pages 2368–2380 (2010)Cite this article

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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)-β1. Smad4 nuclear translocation occurred in response to collagen binding, indicating downstream signal propagation. TGF-β scavenging antibody affected only TGF-β1, but not crosstalk-induced responses. TGF-β type II receptor mutation (DR26Δ25), which is deficient in TGF-β type I receptor recruitment to the ligand, induced a heterotetramer signaling complex, and propagated Smad2 activation only through collagen induction and not TGF-β signaling. Consequentially, TGF-β ligand participation is not required for crosstalk signaling. This signaling requires a functional integrin β1 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-β receptors and integrins. The related gene expressional responses are distinct from that evoked by TGF-β1, supporting its separate function. This signaling mechanism expands and partially explains TGF-β receptor dynamics and consequential signaling diversity-related gene expressional plasticity.

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Acknowledgements

We thank Drs Edward B Leof for the pSmad3-specific antibody, as well as for CCL 64 and R1B cells, Joan Massague for DR26 cells, Mary Goldring for C28 cells and Joel A Block for JJ012 cells. This work was supported by Grants CA-66088Y to SPS from National Institutes of Health, ACS 66105H to NG from the American Cancer Society and by the Woman's Cancer Association Madelon Ravlin Memorial Award WCA 66461Y to NG and SPS. Further support was provided by the University of Miami Orthopaedics Department, and the Sylvester Comprehensive Cancer Center.

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Authors and Affiliations

  1. Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA

    N Garamszegi, S P Garamszegi, E Walford & S P Scully

  2. Department of Orthopaedics, University of Miami Leonard M Miller School of Medicine, Miami, FL, USA

    N Garamszegi, M M Schneiderbauer & S P Scully

  3. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    P Samavarchi-Tehrani & J L Wrana

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Correspondence to N Garamszegi or S P Scully.

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Garamszegi, N., Garamszegi, S., Samavarchi-Tehrani, P. et al. Extracellular matrix-induced transforming growth factor-β receptor signaling dynamics. Oncogene 29, 2368–2380 (2010). https://doi.org/10.1038/onc.2009.514

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