To prevent the dire consequences of uncontrolled activation of tyrosine kinase receptors, such as the epidermal growth factor receptor (EGFR), both extracellular and intracellular controlling mechanisms have been devised during evolution. One such extracellular mechanism of EGFR regulation is provided by decorin, a leucine-rich proteoglycan that binds to and downregulates EGFR activity both in vitro and in vivo. We hypothesized that other soluble forms of proteins harboring leucine-rich repeats could similarly affect the EGFR signaling pathway. Thus, we focused our attention on LRIG1, a transmembrane protein containing fifteen leucine-rich repeats and three Ig-like repeats in its ectodomain. We generated a soluble ectodomain of LRIG1 containing only the leucine-rich repeats and flanking Cys-rich caps. We discovered that nanomolar concentrations of LRIG1 ectodomain inhibit both basal and ligand-dependent EGFR activation and Erk1/2 signaling in a dose-dependent fashion. This, in turn, causes growth inhibition of EGFR-expressing carcinoma cells but not of cells lacking expression of the receptor. Furthermore, we provide genetic evidence for EGFR requirement in the LRIG1-mediated function, and demonstrate the existence of high-affinity (Kd=10 nM) binding sites on the A431 cells, the vast majority (up to 75%) of which can be competitively displaced by EGF. These novel results suggest that the soluble ectodomain of LRIG1, which could conceivably be released at sites of tissue remodeling and tumor invasion, might act as negative regulator of EGFR activity. The central hypothesis of this new grant application is that release of soluble LRIG1 ectodomain from the cell surface around or within carcinomas could represent a biological mechanism to counteract the invading tumor cells, thereby functioning as a natural EGFR antagonist. Specifically, we plan to: ? [1] Decipher the mechanism of action of LRIG1 ectodomain in suppressing EGFR activity, [2] Determine the mechanism of LRIG1-evoked signaling via the EGFR and its ability to inhibit cell growth , and [3] Investigate the in vivo function of LRIG1 ectodomain as an anti-oncogenic factor. ? These concerted research lines should firmly establish the functional roles of LRIG1 in tumorigenicity and shed light on its mechanism of action. The expected results could open novel perspectives for basic cancer research, and could lead to future approaches of cancer treatment by using a natural inhibitor of tumor cell growth. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA120975-01A2
Application #
7314465
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Woodhouse, Elizabeth
Project Start
2007-08-01
Project End
2011-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$235,600
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Gubbiotti, Maria A; Neill, Thomas; Iozzo, Renato V (2017) A current view of perlecan in physiology and pathology: A mosaic of functions. Matrix Biol 57-58:285-298
Iozzo, Renato V; Schaefer, Liliana (2015) Proteoglycan form and function: A comprehensive nomenclature of proteoglycans. Matrix Biol 42:11-55
Theocharis, Achilleas D; Skandalis, Spyros S; Neill, Thomas et al. (2015) Insights into the key roles of proteoglycans in breast cancer biology and translational medicine. Biochim Biophys Acta 1855:276-300
Neill, Thomas; Schaefer, Liliana; Iozzo, Renato V (2015) Decoding the Matrix: Instructive Roles of Proteoglycan Receptors. Biochemistry 54:4583-98
Gubbiotti, Maria A; Neill, Thomas; Frey, Helena et al. (2015) Decorin is an autophagy-inducible proteoglycan and is required for proper in vivo autophagy. Matrix Biol 48:14-25
Willis, Chris D; Poluzzi, Chiara; Mongiat, Maurizio et al. (2013) Endorepellin laminin-like globular 1/2 domains bind Ig3-5 of vascular endothelial growth factor (VEGF) receptor 2 and block pro-angiogenic signaling by VEGFA in endothelial cells. FEBS J 280:2271-84
Buraschi, Simone; Neill, Thomas; Goyal, Atul et al. (2013) Decorin causes autophagy in endothelial cells via Peg3. Proc Natl Acad Sci U S A 110:E2582-91
Neill, Thomas; Jones, Holly R; Crane-Smith, Zoe et al. (2013) Decorin induces rapid secretion of thrombospondin-1 in basal breast carcinoma cells via inhibition of Ras homolog gene family, memberýýA/Rho-associated coiled-coil containing protein kinaseýý1. FEBS J 280:2353-68
Morrione, Andrea; Neill, Thomas; Iozzo, Renato V (2013) Dichotomy of decorin activity on the insulin-like growth factor-I system. FEBS J 280:2138-49
Frey, Helena; Schroeder, Nina; Manon-Jensen, Tina et al. (2013) Biological interplay between proteoglycans and their innate immune receptors in inflammation. FEBS J 280:2165-79

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