Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 15, Pages 3933-3938Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1614894114
Keywords
focal adhesion; myosin; fibronectin; melanoma; cancer
Categories
Funding
- Mayo Clinic
- Gerstner Family
- German Research Foundation [KFO-274]
- National Cancer Institute of the NIH [P50CA108961]
- National Institute of Diabetes and Digestive and Kidney Diseases of the NIH [R01DK083345]
- Carol M. Baldwin Breast Cancer Research Fund of CNY, Inc.
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Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in development and human disease, including cancer. It is currently thought that the four-point one, ezrin, radixin, moesin (FERM)- kinase domain linker, which contains autophosphorylation site tyrosine (Y) 397, is not required for in vivo FAK function until late midgestation. Here, we directly tested this hypothesis by generating mice with FAK Y397-to-phenylalanine (F) mutations in the germline. We found that Y397F embryos exhibited reduced mesodermal fibronectin (FN) and osteopontin expression and died during mesoderm development akin to FAK kinase-dead mice. We identified myosin-1E (MYO1E), an actin-dependent molecular motor, to interact directly with the FAK FERM-kinase linker and induce FAK kinase activity and Y397 phosphorylation. Active FAK in turn accumulated in the nucleus where it led to the expression of osteopontin and other FN-typematrix in both mouse embryonic fibroblasts and human melanoma. Our data support a model in which FAK Y397 autophosphorylation is required for FAK function in vivo and is positively regulated by MYO1E.
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