Oncotarget

Research Papers: Pathology:

The protein kinase LKB1 negatively regulates bone morphogenetic protein receptor signaling

Erna Raja, Kalliopi Tzavlaki, Robin Vuilleumier, Karolina Edlund, Kaoru Kahata, Agata Zieba, Anita Morén, Yukihide Watanabe, Iryna Voytyuk, Johan Botling, Ola Söderberg, Patrick Micke, George Pyrowolakis, Carl-Henrik Heldin and Aristidis Moustakas _

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Oncotarget. 2016; 7:1120-1143. https://doi.org/10.18632/oncotarget.6683

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Abstract

Erna Raja1, Kalliopi Tzavlaki2,*, Robin Vuilleumier3,*, Karolina Edlund4, Kaoru Kahata1, Agata Zieba4, Anita Morén1, Yukihide Watanabe1, Iryna Voytyuk1, Johan Botling4, Ola Söderberg4, Patrick Micke4, George Pyrowolakis3, Carl-Henrik Heldin1 and Aristidis Moustakas1,2

1 Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

2 Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

3 BIOSS, Centre for Biological Signaling Studies and Institute for Biology I, Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany

4 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

* These authors have contributed equally to the work

Correspondence to:

Aristidis Moustakas, email:

Keywords: BMP, differentiation, Drosophila, LKB1, lung cancer, Pathology Section

Received: July 23, 2015 Accepted: December 08, 2015 Published: December 19, 2015

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.


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