title: The protein kinase LKB1 negatively regulates bone morphogenetic protein receptor signaling.
abstract: The protein kinase LKB1 regulates cell metabolism and growth and is implicated in intestinal and lung cancer. Bone morphogenetic protein (BMP) signaling regulates cell differentiation during development and tissue homeostasis. We demonstrate that LKB1 physically interacts with BMP type I receptors and requires Smad7 to promote downregulation of the receptor. Accordingly, LKB1 suppresses BMP-induced osteoblast differentiation and affects BMP signaling in Drosophila wing longitudinal vein morphogenesis. LKB1 protein expression and Smad1 phosphorylation analysis in a cohort of non-small cell lung cancer patients demonstrated a negative correlation predominantly in a subset enriched in adenocarcinomas. Lung cancer patient data analysis indicated strong correlation between LKB1 loss-of-function mutations and high BMP2 expression, and these two events further correlated with expression of a gene subset functionally linked to apoptosis and migration. This new mechanism of BMP receptor regulation by LKB1 has ramifications in physiological organogenesis and disease.
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Erna
authors.initials: E
authors.lastname: Raja
authors.affiliation: Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Tzavlaki
authors.affiliation: BIOSS, Centre for Biological Signaling Studies and Institute for Biology I, Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: Vuilleumier
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Edlund
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kahata
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Agata
authors.initials: A
authors.lastname: Zieba
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Anita
authors.initials: A
authors.lastname: Morén
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Iryna
authors.initials: I
authors.lastname: Voytyuk
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Botling
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Söderberg
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Patrick
authors.initials: P
authors.lastname: Micke
authors.affiliation: BIOSS, Centre for Biological Signaling Studies and Institute for Biology I, Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors.forename: George
authors.initials: G
authors.lastname: Pyrowolakis
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D030801:Animals, Genetically Modified; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004330:Drosophila / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011679:Pupa / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D014921:Wings, Animal / Q000254:growth & development / Q000378:metabolism
chemical_list: D051906:Smad7 Protein; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D052005:Bone Morphogenetic Protein Receptors, Type I
keywords: BMP; Drosophila; LKB1; Pathology Section; differentiation; lung cancer