Journal
GROWTH HORMONE & IGF RESEARCH
Volume 16, Issue 1, Pages 41-48Publisher
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.ghir.2005.09.003
Keywords
insulin-secreting cell; type 1 diabetes; insulin-like growth factor binding protein; apoptosis; tyrosine kinase
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Funding
- NIDDK NIH HHS [K08 DK002876-04, K08 DK002876, K08 DK02876] Funding Source: Medline
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Understanding mechanisms underlying apoptotic destruction of insulin-secreting cells is critical to validate therapeutic targets for type I diabetes mellitus. We recently reported insulin-like growth factor binding protem-3 (IGFBP-3) as a novel mediator of apoptosis in insulin-secreting cells. In light of emerging IGF-independent roles for IGFBP-3, we investigated the mechanisms underlying actions of the novel, recombinant human mutant G(56)G(80)G(81)-IGFBP-3, which lacks intrinsic IGF binding affinity. Using the rat insulinoma RINm5F cell line, we report the first studies in insulin-secreting cells that IGFBP-3 selectively suppresses multiple, key intracellular phosphorelays. By immunoblot, we demonstrate that G(56)G(80)G(81)-IGFBP-3 suppresses phosphorylation of c-raf-MEK-ERK pathway and p38 kinase in time-dependent and dose-dependent manners. SAPK/JNK signaling was unaffected. These data delineate several novel intracellular sites of action for IGFBP-3 in insulin-secreting cells. (c) 2005 Elsevier Ltd. All rights reserved.
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