Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Edited by Richard O. Hynes, Massachusetts Institute of Technology, Cambridge, MA, and approved March 2, 2017 (received for review September 8, 2016)
Significance
Focal adhesion kinase (FAK) is an intensely studied protein involved in many medically relevant biological processes, including cancer. Despite the large interest in FAK, a promising strategy to target FAK therapeutically is elusive. Here, we show that a region within the FAK protein that contains autophosphorylation site tyrosine (Y) 397 is essential for FAK activity in vivo. Myosin-1E (MYO1E), an actin-dependent molecular motor protein, directly interacts with FAK to induce Y397 autophosphorylation, which, in turn, causes changes in gene expression commonly observed in aggressive cancer. Our findings are significant because they further delineate FAK function in vivo and identify the MYO1E–FAK interaction as a possible Achilles’ heel for cancer.
Abstract
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-type matrix 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.
Footnotes
↵1Present address: Department of Chemistry, University of Oslo, 0316 Oslo, Norway.
- ↵2To whom correspondence should be addressed. Email: meves.alexander{at}mayo.edu.
Author contributions: J.B.H., A.N., G.Z., H.Y., R.S., T.S., R.T.B., J.-H.L., T.O., and A.M. designed research; J.B.H., E.J.S., A.N., G.Z., S.S.-D., S.P.W., E.N., H.Y., R.T.B., J.-H.L., and A.M. performed research; J.B.H., A.N., G.Z., N.B., D.M.S., J.L.-A., H.Y., J.N.S., M.K., J.v.D., R.S., T.S., R.T.B., J.-H.L., T.O., and A.M. contributed new reagents/analytic tools; J.B.H., E.J.S., A.N., G.Z., K.S.G., H.Y., T.O., and A.M. analyzed data; and J.B.H. and A.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1614894114/-/DCSupplemental.
Freely available online through the PNAS open access option.
Myosin-1E/FAK induce fibronectin-type matrix
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