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Imatinib mesylate stimulates low-density lipoprotein receptor-related protein 1-mediated ERK phosphorylation in insulin-producing cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2015 (English)In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 128, no 1, 17-28 p.Article in journal (Refereed) Published
Abstract [en]

Low-density lipoprotein receptor-related protein 1 (LRP1) is an endocytic and multi-functional type I cell surface membrane protein, which is known to be phosphorylated by the activated platelet-derived growth factor receptor (PDGFR). The tyrosine kinase inhibitor imatinib, which inhibits PDGFR and c-Abl, and which has previously been reported to counteract beta-cell death and diabetes, has been suggested to reduce atherosclerosis by inhibiting PDGFR-induced LRP1 phosphorylation. The aim of the present study was to study LRP1 function in beta-cells and to what extent imatinib modulates LRP1 activity. LRP1 and c-Abl gene knockdown was performed by RNAi using rat INS-1 832/13 and human EndoC1-beta H1 cells. LRP1 was also antagonized by treatment with the antagonist low-density lipoprotein receptor-related protein associated protein 1 (LRPAP1). We have used PDGF-BB, a PDGFR agonist, and apolipoprotein E (ApoE), an LRP1 agonist, to stimulate the activities of PDGFR and LRP1 respectively. Knockdown or inhibition of LRP1 resulted in increased hydrogen peroxide (H2O2)(-) or cytokine-induced cell death, and glucose-induced insulin release was lowered in LRP1-silenced cells. These results indicate that LRP1 function is necessary for beta-cell function and that LRP1 is adversely affected by challenges to beta-cell health. PDGF-BB, or the combination of PDGF-BB+ApoE, induced phosphorylation of extracellular-signal-regulated kinase (ERK), Akt and LRP1. LRP1 silencing blocked this event. Imatinib blocked phosphorylation of LRP1 by PDGFR activation but induced phosphorylation of ERK. LRP1 silencing blocked imatinib-induced phosphorylation of ERK. Sunitinib also blocked LRP1 phosphorylation in response to PDGF-BB and induced phosphorylation of ERK, but this latter event was not affected by LRP1 knockdown. siRNA-mediated knockdown of the imatinib target c-Abl resulted in an increased ERK phosphorylation at basal conditions, with no further increase in response to imatinib. Imatinib-induced cell survival of tunicamycin-treated cells was partially mediated by ERK activation. We have concluded that imatinib promotes LRP1-dependent ERK activation, possibly via inhibition of c-Abl, and that this could contribute to the pro-survival effects of imatinib on beta-cells.

Place, publisher, year, edition, pages
2015. Vol. 128, no 1, 17-28 p.
Keyword [en]
beta-cell, EndoC1-beta H1, imatinib mesylate, lipoprotein receptor-related protein 1 (LRP1), platelet-derived growth factor receptor (PDGFR)
National Category
Other Clinical Medicine
Identifiers
URN: urn:nbn:se:uu:diva-247177DOI: 10.1042/CS20130560ISI: 000349362800002PubMedID: 24865476OAI: oai:DiVA.org:uu-247177DiVA: diva2:795139
Available from: 2015-03-13 Created: 2015-03-13 Last updated: 2017-12-04Bibliographically approved

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Fred, Rikard G.Welsh, Nils

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