Myosin-1E interacts with FAK proline-rich region 1 to induce fibronectin-type matrix

Joel B. Heim, Edwin J. Squirewell, Ancilla Neu, Georg Zocher, Sindhuja Sominidi-Damodaran, Saranya P. Wyles, Ekaterina Nikolova, Nille Behrendt, Ditte M. Saunte, Jorgen Lock-Andersen, Krutika S. Gaonkar, Huihuang Yan, Jann N. Sarkaria, Mira Krendel, Jan Van Deursen, Remco Sprangers, Thilo Stehle, Ralph T. Böttcher, Jeong Heon Lee, Tamas OrdogAlexander Meves

Research output: Contribution to journalArticle

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3933-3938
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number15
DOIs
StatePublished - Apr 11 2017

Keywords

  • Cancer
  • Fibronectin
  • Focal adhesion
  • Melanoma
  • Myosin

ASJC Scopus subject areas

  • General

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    Heim, J. B., Squirewell, E. J., Neu, A., Zocher, G., Sominidi-Damodaran, S., Wyles, S. P., Nikolova, E., Behrendt, N., Saunte, D. M., Lock-Andersen, J., Gaonkar, K. S., Yan, H., Sarkaria, J. N., Krendel, M., Van Deursen, J., Sprangers, R., Stehle, T., Böttcher, R. T., Lee, J. H., ... Meves, A. (2017). Myosin-1E interacts with FAK proline-rich region 1 to induce fibronectin-type matrix. Proceedings of the National Academy of Sciences of the United States of America, 114(15), 3933-3938. https://doi.org/10.1073/pnas.1614894114