Tiam-1, a GEF for Rac1, plays a critical role in metformin-mediated glucose uptake in C2C12 cells

Ga Young You, Jung Ok Lee, Ji Hae Kim, Nami Kim, Soo Kyung Lee, Ji Wook Moon, Sha Jie, Hye Jeong Lee, Su Jin Kim, Sun-Hwa Park, Hyeon Soo Kim

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11 Citations (Scopus)

Abstract

Metformin is known to stimulate glucose uptake, but the mechanism for this action is not fully understood. In this study, AMPK activators (AICAR and metformin) increased the expression of T-lymphoma invasion and metastasis-inducing protein-1 (Tiam-1), a Rac1 specific guanine nucleotide exchange factor (GEF), mRNA and protein in skeletal muscle C2C12 cells. Metformin increases the serine-phosphorylation of Tiam-1 by AMPK and induces interaction between Tiam-1 and 14-3-3. Pharmacologic inhibition of AMPK blocks this interaction, indicating that 14-3-3 may be required for induction of Tiam-1 by AMPK. Metformin also increases the phosphorylation of p21-activated kinase 1 (PAK1), a direct downstream target of Rac1, dependent on AMPK. Tiam-1 is down-regulated at high glucose concentrations in cultured cells and in the db/db mouse model of hyperglycemia. Furthermore, Tiam-1 knock-down blocked metformin-induced increase in glucose uptake. These findings suggest that metformin promotes cellular glucose uptake in part through Tiam-1 induction.

Original languageEnglish
Pages (from-to)2558-2565
Number of pages8
JournalCellular Signalling
Volume25
Issue number12
DOIs
Publication statusPublished - 2013 Dec 1

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Keywords

  • AMPK
  • GEF
  • Glucose uptake
  • PAK1
  • Tiam-1

ASJC Scopus subject areas

  • Cell Biology

Cite this

You, G. Y., Lee, J. O., Kim, J. H., Kim, N., Lee, S. K., Moon, J. W., Jie, S., Lee, H. J., Kim, S. J., Park, S-H., & Kim, H. S. (2013). Tiam-1, a GEF for Rac1, plays a critical role in metformin-mediated glucose uptake in C2C12 cells. Cellular Signalling, 25(12), 2558-2565. https://doi.org/10.1016/j.cellsig.2013.08.018