uu.seUppsala University Publications
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
Platelet-derived growth factor (PDGF)-induced activation of Erk5 MAP-kinase is dependent on Mekk2, Mek1/2, PKC and PI3-kinase, and affects BMP signaling
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Show others and affiliations
2016 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 28, no 9, p. 1422-1431Article in journal (Refereed) Published
Abstract [en]

Platelet-derived growth factor-BB (PDGF-BB) binds to its tyrosine kinase receptors (PDGFRs) and stimulates mitogenicity and survival of cells of mesenchymal origin. Activation of PDGFRs initiates a number of downstream signaling pathways, including phosphatidyl 3'-inositol kinase (PI3-kinase), phospholipase C gamma and MAP kinase pathways. In this report, we show that Erk5 MAP kinase is activated in response to PDGF-BB in the smooth muscle cell line MOVAS in a manner dependent on Mekk2, Mek1/2, Mek5, PI3-kinase and protein kinase C (PKC). The cooperation of Mek1/2 and Mekk2 in the activation of Erk5, suggests a close co-regulation between the Erk1/2 and Erk5 MAP kinase pathways. Furthermore, we found that classical PKCs are important for Erk5 activation. In addition, we found that PKC zeta interacts with Erk5 and may exert a negative feed-back effect. We observed no nuclear accumulation of Erk5 in response to PDGF-BB stimulation, however, we identified a mechanism by which cytoplasmic Erk5 influences gene expression; Erk5 was essential for PDGF-BB-mediated Smad1/5/8 signaling by stimulating release and/or activation of bone morphogenetic protein(s) (BMPs). Thus, PDGF-BB-induced Erk5 activation involves parallel stimulatory and inhibitory pathways and promotes Smad1/5/8 signaling. (C) 2016 Published by Elsevier Inc.

Place, publisher, year, edition, pages
2016. Vol. 28, no 9, p. 1422-1431
Keywords [en]
Erk5, PDGFR beta, Mekk2, MAP kinase, PKC, Smad
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-302674DOI: 10.1016/j.cellsig.2016.06.013ISI: 000380595500027PubMedID: 27339033OAI: oai:DiVA.org:uu-302674DiVA, id: diva2:967459
Funder
Swedish Cancer Society, 140332Available from: 2016-09-08 Created: 2016-09-08 Last updated: 2019-02-03Bibliographically approved
In thesis
1. Studies of PDGF receptor signaling in vitro and in vivo
Open this publication in new window or tab >>Studies of PDGF receptor signaling in vitro and in vivo
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Platelet-derived growth factor receptor (PDGFR) signaling is essential for proliferation, migration and survival of cells of mesenchymal origin; however, its deregulation has been associated with various diseases, including cancer. The aim of this thesis was to clarify the molecular mechanisms of PDGFR signaling regulation. We have studied PDGFR downregulation, identified the E3 ligases and deubiquitinases (DUBs) acting on the receptor, characterized the role of the downstream effector Erk5, as well as elucidated the role of PDGFRβ isoform in tumor growth and angiogenesis.

As Erk5 activation has been associated with tumorigenesis, it is important to delineate the pathway from activated PDGFR to Erk5. Here, we demonstrate not only a complex mechanism for PDGF-induced Erk5 activation that involves Mek5, Mekk2, Mek1/2, PI3K and classical PKCs, but also a novel function for Erk5 by showing that PDGF-BB affects BMP-Smad signaling in an Erk5 pathway-dependent manner, indicating a crosstalk between tyrosine kinase receptor and serine/threonine receptor signaling.

By investigating PDGFRβ downregulation, we demonstrated that ubiquitination of PDGFRβ, mediated by Cbl-b and c-Cbl, is essential for the receptor internalization, signaling, as well as downstream biological responses. Additionally, as ubiquitination is a reversible post-translational modification, we identified USP4 as one of the DUBs acting on PDGFRβ and discovered that USP4 interacts with PDGFRβ, removing both K48- and K63-linked polyubiquitin chains, and increases its stability, in both normal and cancer cells.

Although several studies have highlighted the therapeutic benefit of PDGFR inhibition in cancer treatment, all available PDGFR kinase inhibitors have secondary targets; consequently, the details underlying the importance of PDGFR in tumorigenesis remain unknown. By targeting specifically PDGFRβ in the stroma of various tumor models, we showed that specific inhibition of PDGFRβ signaling suppresses growth of tumors with high levels of PDGF-BB, whereas the multi-target kinase inhibitor imatinib has less effect, indicating the significance of selective targeting of PDGFRβ.

Our data provide new insights into the molecular events underlying PDGFRβ signaling and downregulation, highlight its importance as cancer therapeutic target and lead the way for further discoveries.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1538
Keywords
PDGF, signaling, cancer, Erk5, kinase, Cbl, ubiquitination, deubiquitinase, pericytes, tumor growth, angiogenesis, low molecular weight inhibitors
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-376248 (URN)978-91-513-0571-4 (ISBN)
Public defence
2019-03-22, B42, Biomedical Center, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2019-02-27 Created: 2019-02-03 Last updated: 2019-03-18

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Tsioumpekou, MariaPapadopoulos, NataliaBurovic, FatimaHeldin, Carl-HenrikLennartsson, Johan
By organisation
Science for Life Laboratory, SciLifeLabLudwig Institute for Cancer Research
In the same journal
Cellular Signalling
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 255 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