Disruptions in epithelial cell adhesion and migration are fundamental to physiologic and pathologic processes such as embryonic development, wound healing, development and progression of cancer. Cadherins and integrins are the central protein receptors in adhesion and migration. Although there appears to be an important relationship between cadherins and integrins their molecular cross-talk is not well characterized, but a promising area of research is the ras-like protein rap1 and its signaling cascade. Recent studies in mouse thyroid and human breast cells support a role for rap1 in the cross-talk between cadherins and integrins. Specifically endocytosed cadherin stimulates rap1, which primes integrin receptors. The latter bind ligands, such as fibronectin, which trigger rad-mediated signaling events to facilitate cell migration. These studies suggest that rap1 plays a critical role in linking cell adhesion and migration via an inside-out signaling mechanism; however, this has not been investigated in keratinocytes. Consistent with this role, our preliminary studies in keratinocytes suggest that active rap1 facilitates adhesion to fibronectin, a possible mechanism for increased migration. E-cadherin-stimulated rap1 may also induce cell migration via nuclear transport of p-catenin, which is released when E-cad is endocytosed. The central hypothesis of this application is that disruption of cell adhesion stimulates rap1, which enhances cell migration of oral keratinocytes via activation of integrin receptors and via nuclear transport of p-cat. The goals of the proposed study are to determine 1) whether disruption of cell-cell adhesion and endocytosis of E-cad stimulate rap1; 2) the role of active rap1 in inside-out signaling to a5p1; 3) the role of E-cad stimulated rap1 in cell migration via a5p1 integrin and p-cat. The proposed studies will identify novel signaling mechanisms through which rap1 integrates cell adhesion, and migration signaling networks in oral keratinocytes. These findings will facilitate the design of rational strategies to treat chronic wounds or tumors of the oral mucosa. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE018512-01
Application #
7302787
Study Section
Special Emphasis Panel (ZRG1-MOSS-E (02))
Program Officer
Shirazi, Yasaman
Project Start
2007-08-01
Project End
2012-06-30
Budget Start
2007-08-01
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$342,000
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dentistry
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Scanlon, Christina Springstead; Banerjee, Rajat; Inglehart, Ronald C et al. (2015) Galanin modulates the neural niche to favour perineural invasion in head and neck cancer. Nat Commun 6:6885
Banerjee, Rajat; Russo, Nickole; Liu, Min et al. (2014) TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer. Nat Commun 5:4527
Banerjee, Rajat; Van Tubergen, Elizabeth A; Scanlon, Christina S et al. (2014) The G protein-coupled receptor GALR2 promotes angiogenesis in head and neck cancer. Mol Cancer Ther 13:1323-33
Inglehart, Ronald C; Scanlon, Christina S; D'Silva, Nisha J (2014) Reviewing and reconsidering invasion assays in head and neck cancer. Oral Oncol 50:1137-43
Liu, Min; Scanlon, Christina Springstead; Banerjee, Rajat et al. (2013) The Histone Methyltransferase EZH2 Mediates Tumor Progression on the Chick Chorioallantoic Membrane Assay, a Novel Model of Head and Neck Squamous Cell Carcinoma. Transl Oncol 6:273-81
Scanlon, C S; Van Tubergen, E A; Inglehart, R C et al. (2013) Biomarkers of epithelial-mesenchymal transition in squamous cell carcinoma. J Dent Res 92:114-21
Scanlon, Christina S; Van Tubergen, Elizabeth A; Chen, Leng-Chun et al. (2013) Characterization of squamous cell carcinoma in an organotypic culture via subsurface non-linear optical molecular imaging. Exp Biol Med (Maywood) 238:1233-41
Van Tubergen, Elizabeth A; Banerjee, Rajat; Liu, Min et al. (2013) Inactivation or loss of TTP promotes invasion in head and neck cancer via transcript stabilization and secretion of MMP9, MMP2, and IL-6. Clin Cancer Res 19:1169-79
Zhang, Xiaoyi; Junior, Carlos Rossa; Liu, Min et al. (2013) Oral squamous carcinoma cells secrete RANKL directly supporting osteolytic bone loss. Oral Oncol 49:119-28
Russo, N; Wang, X; Liu, M et al. (2013) A novel approach to biomarker discovery in head and neck cancer using an autoantibody signature. Oncogene 32:5026-37

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