Logo: to the web site of Uppsala University

uu.sePublications from Uppsala University
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
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.
Show others and affiliations
2016 (English)In: Oncotarget, E-ISSN 1949-2553, Vol. 7, no 2, p. 1120-1143Article 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, p. 1120-1143
Keywords [en]
BMP; differentiation; Drosophila; LKB1; lung cancer; Pathology Section
National Category
Clinical Laboratory Medicine Basic Medicine
Research subject
Pathology
Identifiers
URN: urn:nbn:se:uu:diva-278888DOI: 10.18632/oncotarget.6683ISI: 000369951100005PubMedID: 26701726OAI: oai:DiVA.org:uu-278888DiVA, id: diva2:907118
Funder
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-2005-005428Available from: 2016-02-26 Created: 2016-02-26 Last updated: 2024-01-17Bibliographically approved
In thesis
1. Regulation of cell differentiation and invasion by members of the TGFß family
Open this publication in new window or tab >>Regulation of cell differentiation and invasion by members of the TGFß family
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) signaling pathways are important in embryonic development and tissue homeostasis, but also have complex roles in the context of cancer. TGFβ promotes epithelial to mesenchymal transition (EMT) a physiological developmental process, often hijacked in different types of cancer, eventually leading to cancer cell invasion and metastasis. BMP signaling is involved in bone formation, angiogenesis and neural cell differentiation, but also regulates cancer by inducing EMT and its reversion. 

Liver kinase B1 (LKB1) is a tumor suppressor protein kinase involved in the regulation of cell metabolism, proliferation and polarity. First, we investigated how LKB1 negatively regulates BMP signaling and we demonstrated that LKB1 interacts with one of the BMP type I receptors and mediates its degradation, leading to the inhibition of BMP-induced cell differentiation.

We then focused on the role of LKB1 in the establishment of mammary epithelial polarity. Upon LKB1 depletion, normal mammary epithelial cells lost the ability to form polarized acini, and displayed enhanced TGFβ responses. The use of a chemical inhibitor targeting TGFβ type I receptor restored the formation of acini, therefore we concluded that the contribution of LKB1 to mammary epithelial polarity is dependent on the regulation of autogenous TGFβ signaling.

Glioblastoma (GBM) is a brain malignancy, that is highly invasive and heterogeneous in terms of cell differentiation. TGFβ enhances the self-renewal potential of glioblastoma stem cells (GSCs), while BMP promotes their differentiation towards the astrocytic lineage. In the second part of this thesis, we investigated the role of different effectors downstream of TGFβ/BMP signaling in GBM. 

Snail is a well-established inducer of EMT in carcinomas but in the context of GBM, we demonstrated that Snail was induced by BMP7, and via its interaction with Smad signaling effectors, enhanced BMP while it suppressed TGFβ signaling, thus promoting the astrocytic differentiation of GSCs and suppressing stemness.

Finally, the role of the TGFβ/BMP target gene, CXXC5, was investigated in GBM. CXXC5 expression was enriched in GSCs that express high levels of stem cell markers, and depletion of CXXC5 led to reduced self-renewal capacity of GBM cells. Further analysis indicated that CXXC5 epigenetically regulates stemness-related genes by counteracting the activity of the polycomb repressor complex 2 (PRC2), thus affecting the histone modification pattern on the regulatory elements of these genes. 

Collectively, the thesis provides evidence on mechanisms that regulate cell differentiation by interfering with TGFβ/BMP signaling.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2021. p. 59
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1736
Keywords
TGFβ, BMP, LKB1, signal transduction, cancer
National Category
Cell and Molecular Biology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-438027 (URN)978-91-513-1172-2 (ISBN)
Public defence
2021-05-18, Room C8:305 and via zoom, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2021-04-27 Created: 2021-03-23 Last updated: 2021-05-25

Open Access in DiVA

fulltext(8515 kB)786 downloads
File information
File name FULLTEXT01.pdfFile size 8515 kBChecksum SHA-512
feb0cfb17cc7ea0171199d0298a4bc6128cfb77b0b5958ee33c5663408154c0b59d317b1ca3026982efbe7ad7a1be3a401cbb1c5fdb168651381bf071d2e15a5
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records

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

Search in DiVA

By author/editor
Raja, ErnaTzavlaki, KalliopiEdlund, KarolinaKahata, KaoruZieba, AgataMorén, AnitaWatanabe, YukihideBotling, JohanSöderberg, OlaMicke, PatrickHeldin, Carl-HenrikMoustakas, Aristidis
By organisation
Ludwig Institute for Cancer ResearchMolecular Cell BiologyMolecular and Morphological PathologyDepartment of Immunology, Genetics and PathologyMolecular toolsDepartment of Medical Biochemistry and Microbiology
In the same journal
Oncotarget
Clinical Laboratory MedicineBasic Medicine

Search outside of DiVA

GoogleGoogle Scholar
Total: 786 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 1230 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf