Journal
JOURNAL OF DENTAL RESEARCH
Volume 99, Issue 8, Pages 959-968Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/0022034520917058
Keywords
integrin alpha 5 beta 1; fibronectin; extracellular matrix; cal adhesion kinase; small GTPases; squamous cell carcinoma
Categories
Funding
- National Institutes of Health (NIH)/National Institute of Dental and Craniofacial Research (NIDCR) [DE027551, DE022567]
- University of Michigan-FAPESP [2014/50312-4, 2017/14283-5]
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Cell-cell adhesion is a key mechanism to control tissue integrity and migration. In head and neck squamous cell carcinoma (HNSCC), cell migration facilitates distant metastases and is correlated with poor prognosis. RAP1, a ras-like protein, has an important role in the progression of HNSCC. RAC1 is an integrin-linked, ras-like protein that promotes cell migration. Here we show that loss of cell-cell adhesion is correlated with inactivation of RAP1 confirmed by 2 different biochemical approaches. RAP1 activation is required for cell-matrix adhesion confirmed by adhesion to fibronectin-coated plates with cells that have biochemically activated RAP1. This effect is reversed when RAP1 is inactivated. In addition, RAP1(GTP)-mediated adhesion is only facilitated through alpha 5 beta 1 integrin complex and is not a function of either alpha 5 or beta 1 integrin alone. Moreover, the inside-out signaling of RAP1 activation is coordinated with RAC1 activation. These findings show that RAP1 has a prominent role in cell-matrix adhesion via extracellular matrix molecule fibronectin-induced alpha 5 beta 1 integrin and supports a critical role for the RAP1/RAC1 signaling axis in HNSCC cell migration.
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