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 Ordog

Alexander Meves^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

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
Pages (from-to)	3933-3938
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	15
DOIs	https://doi.org/10.1073/pnas.1614894114
Publication status	Published - 11 Apr 2017

Funding

ACKNOWLEDGMENTS. We thank Reinhard Fässler for valuable discussions and Vincent Truffault for assistance in recording NMR spectra. This work was funded by the Mayo Clinic. It was further supported by Lucille and Smith Gibson, William K. Brokken, Arnold and Kit Palmer, and the Gerstner Family. Additional funding was through the German Research Foundation (Grant KFO-274). J.N.S. is supported by the National Cancer Institute of the NIH under Award P50CA108961. M.K. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH under Award R01DK083345 and a grant from the Carol M. Baldwin Breast Cancer Research Fund of CNY, Inc.

Keywords

Cancer
Fibronectin
Focal adhesion
Melanoma
Myosin

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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

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title = "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.",

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

year = "2017",

month = apr,

day = "11",

doi = "10.1073/pnas.1614894114",

language = "English",

volume = "114",

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journal = "Proceedings of the National Academy of Sciences of the United States of America",

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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 & 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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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.

KW - Cancer

KW - Fibronectin

KW - Focal adhesion

KW - Melanoma

KW - Myosin

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U2 - 10.1073/pnas.1614894114

DO - 10.1073/pnas.1614894114

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AN - SCOPUS:85035241325

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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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