TY - JOUR

T1 - Myosin-1E interacts with FAK proline-rich region 1 to induce fibronectin-type matrix

AU - Heim, Joel B

AU - Squirewell, Edwin J

AU - Neu, Ancilla

AU - Zocher, Georg

AU - Sominidi-Damodaran, Sindhuja

AU - Wyles, Saranya P

AU - Nikolova, Ekaterina

AU - Behrendt, Nille

AU - Saunte, Ditte M

AU - Lock-Andersen, Jorgen

AU - Gaonkar, Krutika S

AU - Yan, Huihuang

AU - Sarkaria, Jann N

AU - Krendel, Mira

AU - van Deursen, Jan

AU - Sprangers, Remco

AU - Stehle, Thilo

AU - Böttcher, Ralph T

AU - Lee, Jeong-Heon

AU - Ordog, Tamas

AU - Meves, Alexander

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1614894114

DO - 10.1073/pnas.1614894114

M3 - Journal article

C2 - 28348210

VL - 114

SP - 3933

EP - 3938

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 15

ER -