Myosin-1E interacts with FAK proline-rich region 1 to induce fibronectin-type matrix
Joel B Heim1, Edwin J Squirewell1, Ancilla Neu2
1Department of Dermatology, Mayo Clinic, Rochester, MN 55905.
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.
Insights
Focal adhesion kinase (FAK) autophosphorylation at tyrosine 397 is crucial for embryonic development. Myosin-1E (MYO1E) activates FAK, promoting matrix gene expression and survival.
Area of Science:
- Cell biology
- Molecular biology
- Developmental biology
Background:
- Focal adhesion kinase (FAK) is a key regulator in cellular processes and disease.
- The role of FAK's autophosphorylation site, tyrosine 397 (Y397), in early development is not fully understood.
Purpose of the Study:
- To investigate the in vivo requirement of FAK Y397 autophosphorylation during embryonic development.
- To identify regulators of FAK Y397 phosphorylation and its downstream effects.
Main Methods:
- Generation of mice with germline FAK Y397-to-phenylalanine (Y397F) mutations.
- Analysis of embryonic lethality, gene expression (fibronectin, osteopontin), and protein interactions.
- Investigated the role of myosin-1E (MYO1E) in FAK activation.
Main Results:
- FAK Y397F mutant embryos exhibited developmental defects and embryonic lethality during mesoderm formation.
- Reduced expression of mesodermal fibronectin and osteopontin was observed in Y397F embryos.
- Myosin-1E (MYO1E) was identified as an interactor that promotes FAK kinase activity and Y397 phosphorylation.
- Active FAK localized to the nucleus, driving osteopontin and fibronectin-type matrix expression.
Conclusions:
- FAK Y397 autophosphorylation is essential for FAK function in vivo during early embryonic development.
- MYO1E positively regulates FAK Y397 autophosphorylation, impacting matrix gene expression and cell survival.
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