Abstract
Differential subcellular localization of EBP50 leads to its controversial role in cancer biology either as a tumor suppressor when it resides at the membrane periphery, or a tumor facilitator at the nucleus. However, the mechanism behind nuclear localization of EBP50 remains unclear. A RNA interference screening identified the downstream effector of the Ras-ERK cascade, RSK1, as the molecule unique for nuclear transport of EBP50. RSK1 binds to EBP50 and phosphorylates it at a conserved threonine residue at position 156 (T156) under the regulation of growth factor. Mutagenesis experiments confirmed the significance of T156 residue in nuclear localization of EBP50, cellular proliferation, and oncogenic transformation. Our study sheds light on a possible therapeutic strategy targeting at this aberrant nuclear expression of EBP50 without affecting the normal physiological function of EBP50 at other subcellular localization.
Highlights
Cellular proteins exert distinct functions depending on their localizations in differential subcellular compartments, where they may possess preferential alterations in their post-translational modifications and/or interaction with other signaling molecules
To discover the signaling pathway governing the nucleocytoplasmic transport of EBP50, we generated a HeLa cell clone that stably expressed enhanced green fluorescent protein (EGFP)-tagged EBP50 (HeLa-EGFP-EBP50)
This cell line was subjected to an arrayed RNA interference (RNAi) screening (Figure 1A) based on the premise that post-translational modification of EBP50, a highly phosphorylated protein, would likely affect its subcellular localization
Summary
Cellular proteins exert distinct functions depending on their localizations in differential subcellular compartments, where they may possess preferential alterations in their post-translational modifications and/or interaction with other signaling molecules. An understanding of the mechanism for subcellular localization of disease-related signaling proteins is, important for diagnosis and therapeutic interventions. Ezrin-radixin-moesin (ERM)-binding phosphoprotein of 50 kDa (EBP50), a scaffold protein that is expressed at the apical surface of luminal organs, consists of two tandem postsynaptic density 95/disks large/. Zona occludens (PDZ) domains and a C-terminal ezrin binding site [5]. The PDZ domains of EBP50 preferably recognize the C-terminal PDZ binding motif (S/T)XL of its interacting partners to organize molecules into functional complexes at the membrane periphery [6].
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