Novel Insights into Integrin α11 Expression and Function
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Integrins are a major group of cell surface receptors, which link the extracellular matrix with the cell cytoskeleton. They are heterodimeric proteins consisting of non- covalently bound α- and β-subunits. By regulating mechanotransduction at cell-ECM communication sites, integrins can also activate many intracellular signaling events, which are essential for cell proliferation, cell migration and gene regulation. Integrin α11β1 is a collagen-binding integrin, which expressed on subsets of fibroblasts. Recent data demonstrated that integrin α11b1 is involved in myofibroblast differentiation and in wound healing, but also is pro-tumorigenic in the tumor stroma and pro-fibrotic in fibrosis. However, detailed molecular insights underlying integrin α11β1 expression, distribution and function in the context of tissue reorganization remains to be determined. In this thesis, we used three different approaches to further characterize integrin α11 expression and function at both cellular and molecular level. Firstly, we investigated the functional role of integrin α11 cytoplasmic tail by deleting last 17 carboxyterminal amino acids in the α11 protein. We found that the cytoplasmic tail of α11 is important for collagen-dependent focal contact formation, collagen remodeling, cell proliferation and cell migration (Paper 1). Later, we generated and characterized a novel transgenic (ITGA11-Cre) mouse strain. Our results demonstrate that the activity of the 3 kb ITGA11 promoter driven Cre-recombinase in the ITGA11-Cre mouse is sufficient to replicate the endogenous expression of integrin a11 both during embryonic development and in fibrotic conditions including cardiac fibrosis and wound healing, respectively (Paper 2). Finally, we used newly developed monoclonal antibody (mAb) to human integrin a11 chain to demonstrate that α11 expression is present on different subset(s) of CAFs in the tumor microenvironment and a11b1 is involved in collagen remodeling and CAF migration in vitro (Paper 3). In summary, this thesis provides new understanding of integrin α11β1 functions in different subsets of fibroblasts in the context of tissue reorganization events including fibrosis and tumor-stroma interactions.
Består avPaper I: Pugazendhi Erusappan, Jahedul Alam, Ning Lu, Cédric Zeltz and Donald Gullberg (2019) Integrin α11 cytoplasmic tail is required for FAK activation to intitate 3D cell invasion and ERK-mediated cell proliferation. Scientific Reports 9, 15283. The article is not available in the thesis file. The article is available at: https://doi.org/10.1038/s41598-019-51689-6.
Paper II: Jahedul Alam, Musiime Moses, Andreas Romaine, Mugdha Sawant, Arne Olav Melleby, Ning Lu, Beate Eckes, Geir Christensen and Donald Gullberg. Characterization of an integrin ITGA11-Cre mouse strain with Cre recombinase expression restricted to fibroblasts. The article is not available in the thesis file.
Paper III: Cédric Zeltz, Jahedul Alam, Hengshuo Liu, Pugazendhi Erusappan, Heinz Hoschuetzky, Anders Molven, Himalaya Parajuli, Edna Cukierman, Daniela-Elena Costea, Ning Lu and Donald Gullberg (2019) α11β1 Integrin is induced in a subset of cancer-associated fibroblasts in desmoplastic tumor stroma and mediates in vitro cell migration. Cancers 11, 765. The article is available in the thesis file. The article is also available at: https://doi.org/10.3390/cancers11060765.