The dynamic and stress-adaptive signaling hub of 14-3-3: emerging mechanisms of regulation and context-dependent protein-protein interactions

Oncogene. 2018 Oct;37(42):5587-5604. doi: 10.1038/s41388-018-0348-3. Epub 2018 Jun 18.


14-3-3 proteins are a family of structurally similar phospho-binding proteins that regulate essentially every major cellular function. Decades of research on 14-3-3s have revealed a remarkable network of interacting proteins that demonstrate how 14-3-3s integrate and control multiple signaling pathways. In particular, these interactions place 14-3-3 at the center of the signaling hub that governs critical processes in cancer, including apoptosis, cell cycle progression, autophagy, glucose metabolism, and cell motility. Historically, the majority of 14-3-3 interactions have been identified and studied under nutrient-replete cell culture conditions, which has revealed important nutrient driven interactions. However, this underestimates the reach of 14-3-3s. Indeed, the loss of nutrients, growth factors, or changes in other environmental conditions (e.g., genotoxic stress) will not only lead to the loss of homeostatic 14-3-3 interactions, but also trigger new interactions, many of which are likely stress adaptive. This dynamic nature of the 14-3-3 interactome is beginning to come into focus as advancements in mass spectrometry are helping to probe deeper and identify context-dependent 14-3-3 interactions-providing a window into adaptive phosphorylation-driven cellular mechanisms that orchestrate the tumor cell's response to a variety of environmental conditions including hypoxia and chemotherapy. In this review, we discuss emerging 14-3-3 regulatory mechanisms with a focus on post-translational regulation of 14-3-3 and dynamic protein-protein interactions that illustrate 14-3-3's role as a stress-adaptive signaling hub in cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 14-3-3 Proteins / metabolism*
  • Animals
  • Humans
  • Signal Transduction / physiology*
  • Stress, Physiological / physiology*


  • 14-3-3 Proteins