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

Abstract

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.

Intelligent Design of 14-3-3 Docking Proteins Utilizing Synthetic Evolution Artificial Intelligence (SYN-AI)

“…The aforementioned is significant in that interaction of globular domains of protein interaction partners within the 14-3-3 amphipathic grove regulate stress signaling proteins such as ERK, MAPK, JNK and p38 MAPK as well as growth and cell cycle regulators raf, PI3K and cdc25 phosphatase. [45][46][47][48][49][61][62][63][64][65][66][67] We confirmed conservation of these ligand binding interactions as well as confirmed the conservation of intra protein communication by analyzing allosteric effects utilizing the elastic network model. Whereby, normal mode analysis of parental and synthetic 14-3-3 ζ docking proteins was performed utilizing ElNemo and ANM2.1.…”

“…11 Whereby, 14-3-3 proteins have been shown to interact with key signaling components such as the insulin like growth receptor [57][58][59] , PI3K 60, 61 , cdc25 phosphatase [62][63][64] , and bad. [65][66][67] .…”

Spatial and temporal alterations in protein structure by EGF regulate cryptic cysteine oxidation

“…6A), well below the 17 threshold of 25% that is considered solvent accessible (68). This surprising observation is 18 consistent with Yang et al (96) since evaluating their dataset with the same solvent prediction The 14-3-3 protein family consists of 7 highly conserved genes that bind phospho-1 serine/phospho-threonine motifs, interact with EGFR, and promote EGFR signaling (62,67). 8 of 2 9 peptides detected in 14-3-3 proteins were significantly oxidized by EGF (Fisher's p=7e -7 ), 3 most notably oxidation of a highly conserved cysteine in helix 4 in five of the six 14-3-3 family 4 members detected ( Fig.…”

A Supramolecular Stabilizer of the 14‐3‐3ζ/ERα Protein‐Protein Interaction with a Synergistic Mode of Action

“…Members of the 14‐3‐3 protein family are regulatory adapter elements in intracellular signaling pathways by means of recognition of proteins that contain phosphorylated Ser/Thr residues like those implicated in the MAPK (mitogen‐activated protein kinase) pathway . As a measure of their relevance, more than 300 potential binding partners of this family have been identified.…”