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.
authors.affiliation: Department of Dermatology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Joel B
authors.initials: JB
authors.lastname: Heim
authors.affiliation: Department of Dermatology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Squirewell
authors.affiliation: Max Planck Institute for Developmental Biology, 72076 Tuebingen, Germany.
authors.forename: Ancilla
authors.initials: A
authors.lastname: Neu
authors.affiliation: Interfaculty Institute of Biochemistry, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Zocher
authors.affiliation: Department of Dermatology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Sindhuja
authors.initials: S
authors.lastname: Sominidi-Damodaran
authors.affiliation: Department of Dermatology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Saranya P
authors.initials: SP
authors.lastname: Wyles
authors.affiliation: Department of Dermatology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Nikolova
authors.affiliation: Department of Pathology, University of Copenhagen, Roskilde Hospital, DK-4000 Roskilde, Denmark.
authors.forename: Nille
authors.initials: N
authors.lastname: Behrendt
authors.affiliation: Department of Dermatology, University of Copenhagen, Roskilde Hospital, DK-4000 Roskilde, Denmark.
authors.forename: Ditte M
authors.initials: DM
authors.lastname: Saunte
authors.affiliation: Department of Plastic Surgery, University of Copenhagen, Roskilde Hospital, DK-4000 Roskilde, Denmark.
authors.forename: Jorgen
authors.initials: J
authors.lastname: Lock-Andersen
authors.affiliation: Division of Biostatistics and Informatics, Department of Health Science Research, Mayo Clinic, Rochester, MN 55905.
authors.forename: Krutika S
authors.initials: KS
authors.lastname: Gaonkar
authors.affiliation: Division of Biostatistics and Informatics, Department of Health Science Research, Mayo Clinic, Rochester, MN 55905.
authors.forename: Huihuang
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.affiliation: Cell and Developmental Biology, SUNY Upstate Medical University, Syracuse, NY 13210.
authors.forename: Mira
authors.initials: M
authors.lastname: Krendel
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905.|Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905.|Mayo Clinic Cancer Center, Rochester, MN 55905.
authors.forename: Jan
authors.initials: J
authors.lastname: van Deursen
authors.affiliation: Max Planck Institute for Developmental Biology, 72076 Tuebingen, Germany.
authors.forename: Remco
authors.initials: R
authors.lastname: Sprangers
authors.affiliation: Interfaculty Institute of Biochemistry, University of Tuebingen, 72076 Tuebingen, Germany.|Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Thilo
authors.initials: T
authors.lastname: Stehle
authors.affiliation: Department of Molecular Medicine, Max Planck Institute for Biochemistry, 82152 Martinsried, Germany.|German Center for Cardiovascular Research-Munich Partner Site, 80802 Munich, Germany.
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Böttcher
authors.affiliation: Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905.
authors.forename: Jeong-Heon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905.
authors.forename: Tamas
authors.initials: T
authors.lastname: Ordog
authors.affiliation: Department of Dermatology, Mayo Clinic, Rochester, MN 55905; meves.alexander@mayo.edu.|Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905.|Mayo Clinic Cancer Center, Rochester, MN 55905.
authors.forename: Alexander
authors.identifier: 0000-0001-7462-8288
authors.initials: A
authors.lastname: Meves
mesh_terms: D000818:Animals; D020964:Embryo Loss / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D008648:Mesoderm / Q000196:embryology; D008817:Mice, Mutant Strains; D024461:Myosin Type I; D009218:Myosins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D000072417:Protein Domains; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D014443:Tyrosine / Q000378:metabolism
chemical_list: D005353:Fibronectins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D014443:Tyrosine; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; C505821:Myo1e protein, mouse; D024461:Myosin Type I; D009218:Myosins
keywords: cancer; fibronectin; focal adhesion; melanoma; myosin