The protein kinase LKB1 negatively regulates bone morphogenetic protein receptor signaling

• Published in: Oncotarget 2016-01, Vol.7 (2), p.1120-1143
• Main Authors: Raja, Erna, Tzavlaki, Kalliopi, Vuilleumier, Robin, Edlund, Karolina, Kahata, Kaoru, Zieba, Agata, Morén, Anita, Watanabe, Yukihide, Voytyuk, Iryna, Botling, Johan, Söderberg, Ola, Micke, Patrick, Pyrowolakis, George, Heldin, Carl-Henrik, Moustakas, Aristidis
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Bone Morphogenetic Protein Receptors, Type I - genetics; Bone Morphogenetic Protein Receptors, Type I - metabolism; Cell Line; Cell Line, Tumor; Cells, Cultured; Drosophila - genetics; Drosophila - growth & development; Drosophila - metabolism; Gene Expression; HEK293 Cells; Humans; Immunoblotting; Immunohistochemistry; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice, Knockout; Pathology; Patologi; Protein Binding; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Pupa - genetics; Pupa - growth & development; Pupa - metabolism; Research Paper: Pathology; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Smad7 Protein - genetics; Smad7 Protein - metabolism; Wings, Animal - growth & development; Wings, Animal - metabolism
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.6683

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.