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The protein kinase LKB1 negatively regulates bone morphogenetic protein receptor signaling
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Molecular Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 2, 1120-1143 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 7, no 2, 1120-1143 p.
Keyword [en]
BMP; differentiation; Drosophila; LKB1; lung cancer; Pathology Section
National Category
Clinical Laboratory Medicine Basic Medicine
Research subject
URN: urn:nbn:se:uu:diva-278888DOI: 10.18632/oncotarget.6683ISI: 000369951100005PubMedID: 26701726OAI: diva2:907118
Swedish Research Council, K2007-66X-14936-04-3Swedish Research Council, K2010-67X-14936-07-03Swedish Research Council, K2013-66X-14936-10-5EU, European Research Council, MRTN-2005-005428
Available from: 2016-02-26 Created: 2016-02-26 Last updated: 2016-04-01Bibliographically approved

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Tzavlaki, KalliopiZieba, AgataMorén, AnitaBotling, JohanSöderberg, OlaMicke, PatrickHeldin, Carl-HenrikMoustakas, Aristidis
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