14-3-3 proteins as potential therapeutic targets

Abstract

The 14-3-3 family of phosphoserine/phosphothreonine-binding proteins dynamically regulates the activity of client proteins in various signaling pathways that control diverse physiological and pathological processes. In response to environmental cues, 14-3-3 proteins orchestrate the highly regulated flow of signals through complex networks of molecular interactions to achieve well-controlled physiological outputs, such as cell proliferation or differentiation. Accumulating evidence now supports the concept that either an abnormal state of 14-3-3 protein expression, or dysregulation of 14-3-3/client protein interactions, contributes to the development of a large number of human diseases. In particular, clinical investigations in the field of oncology have demonstrated a correlation between upregulated 14-3-3 levels and poor survival of cancer patients. These studies highlight the rapid emergence of 14-3-3 proteins as a novel class of molecular target for potential therapeutic intervention. The current status of 14-3-3 modulator discovery is discussed.

Parkinson-related LRRK2 mutation R1441C/G/H impairs PKA phosphorylation of LRRK2 and disrupts its interaction with 14-3-3

“…Dysregulation of 14-3-3/target protein interaction has been associated with several human disorders, including PD, establishing 14-3-3 proteins as a novel class of molecules for therapeutic intervention (44). In agreement with the findings by Li et al (12) and Nichols et al (19), we demonstrate that 14-3-3 binding is impaired in the common familiar LRRK2 mutation R1441C/G/H.…”

14-3-3 proteins are essential signalling hubs for beta cell survival

“…Our observations raise the possibility that therapeutic approaches, designed to increase the levels or activity of 14-3-3 proteins, could protect beta cells from death during diabetes [2]. Interestingly, the inhibition of 14-3-3 proteins has been proposed as a potential novel approach for the treatment of some cancers [48], an approach that, based on our results, could have deleterious effects on beta cell survival and potentially on glucose homeostasis. Further work is therefore required to evaluate the role of 14-3-3 proteins in other tissues important for glucose homeostasis.…”

Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: Potential roles in GABAergic interneuron pathology

“…Therefore, therapeutics targeting 14-3-3 signaling directly (Zhao et al, 2011) could represent a future avenue in protecting the hippocampal neuron populations from damage in psychiatric disorders.…”