| First Author | Gao FJ | Year | 2017 |
| Journal | Mol Biol Cell | Volume | 28 |
| Issue | 5 | Pages | 587-599 |
| PubMed ID | 28057765 | Mgi Jnum | J:240425 |
| Mgi Id | MGI:5883382 | Doi | 10.1091/mbc.E16-07-0555 |
| Citation | Gao FJ, et al. (2017) Insulin signaling regulates a functional interaction between adenomatous polyposis coli and cytoplasmic dynein. Mol Biol Cell 28(5):587-599 |
| abstractText | 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-3beta (GSK-3beta), which could shed light on this issue. GSK-3beta 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 beta-catenin by GSK-3beta cause colorectal cancer in humans. Of interest, both APC and GSK-3beta interact with microtubules and cellular membranes. We recently demonstrated that dynein is a GSK-3beta substrate and that inhibition of GSK-3beta promotes dynein-dependent transport. We now report that dynein stimulation in intestinal cells in response to acute insulin exposure (or GSK-3beta 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. |
