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

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.

authors

Heim JB,Squirewell EJ,Neu A,Zocher G,Sominidi-Damodaran S,Wyles SP,Nikolova E,Behrendt N,Saunte DM,Lock-Andersen J,Gaonkar KS,Yan H,Sarkaria JN,Krendel M,van Deursen J,Sprangers R,Stehle T,Böttcher RT,Lee JH,Ordog T

doi

10.1073/pnas.1614894114

subject

Has Abstract

pub_date

2017-04-11 00:00:00

pages

3933-3938

issue

15

eissn

0027-8424

issn

1091-6490

pii

1614894114

journal_volume

114

pub_type

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