Paula J. McKeown-Longo
Muntz Professor and Director
University of Connecticut
Chronic inflammation and tissue fibrosis are believed to be major contributors to the development and progression of solid tumors. Tumor progression is accompanied by extensive biochemical and mechanical remodeling of the fibronectin matrix within the tumor stroma. This remodeling includes the upregulation of the EDA isoform of fibronectin, proteolytic release of fibronectin fragments and mechanically induced changes in fibronectin secondary structure. The contribution of this remodeling to the initiation and maintenance of tissue inflammation and fibrosis is not well understood. Structurally, fibronectin is organized into independently folded domains, termed Type I, II and III. These domains can function as ligands for cell surface receptors and as binding sites for other matrix molecules, cytokines and growth factors. Our laboratory is studying the role of specific fibronectin Type III domains in the expression of inflammatory cytokines and matrix remodeling genes by stromal fibroblasts. We have identified the Type III-1 and alternatively spliced EDA domains of fibronectin as ligands for Toll-like Receptors (TLRs) on fibroblast cells. Current projects are focused on the identification and characterization of the TLR complexes and downstream signaling pathways which regulate expression of inflammatory and fibrotic proteins in response to fibronectin.
- Shinde, A.V., Kelsh, R., Peters, J.H., Sekiguchi, K., Van De Water, L., and McKeown-Longo, P.J.: The alpha4/beta1 integrin and the EDA domain of fibronectin regulate a profibrotic phenotpye in dermal fibroblasts. Matrix Biol. 2014 Nov. 26. pii:S0945-053X(14)00216-0. doi: 10.1016/j.matbio.2014.11.004 [Epub ahead of print]
- Kelsh, R., You, R., Horzempa, C., Zheng, M., and McKeown-Longo, P.J.: Regulation of the innate immune response by fibronectin: synergism between the III-1 and EDA domains. PLoS One 9:e102974, 2014.
- Ambesi, A. and McKeown-Longo, P.J.: Conformational remodeling of the fibronectin matrix selectively regulates VEGF signaling. J. Cell Sci. 127:3805-3816, 2014.
- Kelsh, R.M. and McKeown-Longo, P.J.: Topographical changes in extracellular matrix: Activation of TLR4 signaling and solid tumor progression. Trends Cancer Res. 9:1-13, 2013.
- Vial, D. and McKeown-Longo, P.J.: Epidermal growth factor (EGF) regulates alpha5/beta1 integrin activation state in human cancer cell lines through p90RSK-dependent phosphorylation of filamin A. J. Biol. Chem. 287:40371-40380, 2012.
- Zheng, M., Jones, D.M., Horzempa, C., Prasad, A., and McKeown-Longo, P.J.: The first type III domain of fibronectin is associated with the expression of cytokines within the lung tumor microenvironment. J. Cancer 2:478-483, 2011.
- You, R., Zheng, M. and McKeown-Longo, P.J.: The first type III repeat in fibronectin activates an inflammatory pathway in dermal fibroblasts. J. Biol. Chem. 285:36255-36259, 2010.
- You, R., Klein, R.M., Zheng, M., and McKeown-Longo, P.J.: Regulation of p38 MAP kinase by anastellin is independent of anastellin's effect on matrix fibronectin. Matrix Biol. 28:101-109, 2009.
- Ambesi, A. and McKeown-Longo, P.J.: Anastellin, the angiostatic fibronectin peptide, is a selective inhibitor of lysophospholipid signaling. Mol. Cancer Res. 7:255-265, 2009.
- Monaghan-Benson, E., Mastick, C.C., and McKeown-Longo, P.J.: A dual role for caveolin-1 in the regulation of fibronectin matrix assembly by uPAR. J. Cell Sci. 121:3693-3703, 2008.