title: Imatinib mesylate stimulates low-density lipoprotein receptor-related protein 1-mediated ERK phosphorylation in insulin-producing cells.
abstract: 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 β-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 β-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-βH1 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 β-cell function and that LRP1 is adversely affected by challenges to β-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 β-cells.
authors.affiliation: *Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Rikard G
authors.initials: RG
authors.lastname: Fred
authors.affiliation: *Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Boddeti
authors.affiliation: *Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Lundberg
authors.affiliation: *Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Nils
authors.initials: N
authors.lastname: Welsh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D000068877:Imatinib Mesylate; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000187:drug effects* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016315:Proto-Oncogene Proteins c-abl / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats
chemical_list: D001549:Benzamides; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D020929:Mitogen-Activated Protein Kinase Kinases