title: Insulin signaling regulates a functional interaction between adenomatous polyposis coli and cytoplasmic dynein.
abstract: Diabetes is linked to an increased risk for colorectal cancer, but the mechanistic underpinnings of this clinically important effect are unclear. Here we describe an interaction between the microtubule motor cytoplasmic dynein, the adenomatous polyposis coli tumor suppressor protein (APC), and glycogen synthase kinase-3β (GSK-3β), which could shed light on this issue. GSK-3β is perhaps best known for glycogen regulation, being inhibited downstream in an insulin-signaling pathway. However, the kinase is also important in many other processes. Mutations in APC that disrupt the regulation of β-catenin by GSK-3β cause colorectal cancer in humans. Of interest, both APC and GSK-3β interact with microtubules and cellular membranes. We recently demonstrated that dynein is a GSK-3β substrate and that inhibition of GSK-3β promotes dynein-dependent transport. We now report that dynein stimulation in intestinal cells in response to acute insulin exposure (or GSK-3β inhibition) is blocked by tumor-promoting isoforms of APC that reduce an interaction between wild-type APC and dynein. We propose that under normal conditions, insulin decreases dynein binding to APC to stimulate minus end-directed transport, which could modulate endocytic and secretory systems in intestinal cells. Mutations in APC likely impair the ability to respond appropriately to insulin signaling. This is exciting because it has the potential to be a contributing factor in the development of colorectal cancer in patients with diabetes.
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21025.
authors.forename: Feng J
authors.initials: FJ
authors.lastname: Gao
authors.affiliation: Department of Biological Sciences, University of South Carolina, Columbia, SC 29208.
authors.forename: Liang
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Biological Sciences, University of South Carolina, Columbia, SC 29208.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hines
authors.affiliation: Department of Anesthesiology and Critical Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
authors.forename: Sachin
authors.initials: S
authors.lastname: Hebbar
authors.affiliation: Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045.
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Neufeld
authors.affiliation: Department of Biological Sciences, University of South Carolina, Columbia, SC 29208 deannasm@biol.sc.edu.
authors.forename: Deanna S
authors.initials: DS
authors.lastname: Smith
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D056445:Cytoplasmic Dyneins / Q000378:metabolism*; D048909:Diabetes Complications / Q000378:metabolism; D005260:Female; D017491:Genes, APC / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism
chemical_list: D007328:Insulin; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D056445:Cytoplasmic Dyneins