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 Ordog; Alexander Meves

doi:10.1073/pnas.1614894114

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

Department of Clinical Medicine

10 Citations (Scopus)

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 language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	15
Pages (from-to)	3933-3938
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1614894114
Publication status	Published - 11 Apr 2017

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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

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, J-H, Ordog, T & 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, vol. 114, no. 15, pp. 3933-3938. https://doi.org/10.1073/pnas.1614894114

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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.",

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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 - 2017/4/11

Y1 - 2017/4/11

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

SN - 0027-8424

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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

IS - 15

ER -

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

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