Biochemical Journal

Review article

The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation

Lars P. van der HEIDE, Marco F. M. HOEKMAN, Marten P. SMIDT

Abstract

FoxO (forkhead box O; forkhead members of the O class) are transcription factors that function under the control of insulin/insulin-like signalling. FoxO factors have been associated with a multitude of biological processes, including cell-cycle, cell death, DNA repair, metabolism and protection from oxidative stress. Central to the regulation of FoxO factors is a shuttling system, which confines FoxO factors to either the nucleus or the cytosol. Shuttling of FoxO requires protein phosphorylation within several domains, and association with 14-3-3 proteins and the nuclear transport machinery. Description of the FoxO-shuttling mechanism contributes to the understanding of FoxO function in relation to signalling and gene regulation.

  • forkhead
  • 14-3-3 protein
  • insulin
  • protein kinase B (PKB)
  • shuttling

Footnotes

  • Abbreviations used: AR androgen receptor; CBP, CREB-binding protein; C/EBPβ, CCAAT/Enhancer binding protein β; CREB, cAMP-response-element-binding protein; CK1, protein kinase CK1 (formerly known as casein kinase 1); CRM1, chromosomal region maintenance protein 1; dFOXO, Drosophila FOXO; dPRL, decidual prolactin; DYRK, dual-specificity regulated kinase; ER, oestrogen receptor; ES, embryonic stem; FoxO, forkhead box O; FKHR, forkhead in rhabdomyosarcoma; G6pc, glucose-6-phosphatase; HNF-4, hepatocyte nuclear factor-4; IGF, insulin-like growth factor; IGFBP-1, IGF-1-binding protein; IRS(1), insulin receptor substrate (1); KIX, kinase-inducible interaction; LMB, leptomycin B; NES, nuclear export sequence; NLS, nuclear localization sequence; PAX(3/7), paired box 3 or 7 respectively; PDK1, phosphoinositide-dependent kinase 1; PGC-1α, proliferative-activated receptor-γ co-activator 1; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PKB, protein kinase B; PTEN, phosphatase and tensin homologue deleted on chromosome 10; RAR, retinoic acid receptor; RCC1, regulator of chromosome condensation; SGK, serum and glucocorticoid-regulated kinase; SRC, steroid receptor co-activator.