The protein kinase LKB1 negatively regulates bone morphogenetic protein receptor signaling.

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

doi:10.18632/oncotarget.6683

Erna Raja, Johan Botling + Show 13 more

Open Access

https://doi.org/10.18632/oncotarget.6683

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Journal: Oncotarget	Publication Date: Dec 19, 2015
Citations: 17	License type: cc-by

Affiliation: Uppsala University, University of Freiburg

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.

Highlights

Bone morphogenetic proteins (BMPs) are evolutionarily conserved members of the transforming growth factor β (TGFβ) family that regulate cell growth, differentiation and apoptosis during development and adult tissue homeostasis [1,2,3]
Reconstitution of Lkb1 into mouse embryonic fibroblasts (MEFs) from Lkb1 knockout mice together with its obligatory cofactors Stradα and Mo25 (LSM; Lkb1/Stradα/Mo25), reduced the physiological induction of endogenous Id1 mRNA by BMP7 almost by half (Figure 1A), and reduced the BMP7-induced activity of the BRE2 promoter (Figure 1B)
Using the Lkb1 knockout MEFs, the HaCaT and A549 cells we demonstrated that expression of single LKB1 kinase components, LKB1, STRADα or MO25 could lead to weaker but detectable downregulation of BMP7 signaling, the efficiency was dramatically enhanced when all three kinase components were coexpressed in the form of LSM (Supplementary Figure 1A1C)

Summary

Introduction

Bone morphogenetic proteins (BMPs) are evolutionarily conserved members of the transforming growth factor β (TGFβ) family that regulate cell growth, differentiation and apoptosis during development and adult tissue homeostasis [1,2,3]. BMPs signal through binding to type I and type II transmembrane serine/threonine kinase receptors [6, 7]. The BMP type II receptors consist of BMPRII, ActRIIA and ActRIIB, and the BMP type I receptors are BMPRIA (or activin receptor-like kinase 3; ALK3), BMPRIB (ALK6), ACVR1 (ALK2) and ACVRL1 (ALK1) [1, 3]. Distinct BMP ligands have different binding affinities for the type I receptors. Homo- and heterodimers of the BMP family ligands dpp www.impactjournals.com/oncotarget (decapentaplegic), scw (screw), and gbb (glass bottom boat) signal via combinations of the type II receptors punt and wit (wishfull thinking) and the type I receptors tkv (thickveins) and sax (saxophone) [10, 11]

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