The 14-3-3 proteins: integrators of diverse signaling cues that impact cell fate and cancer development

Abstract

The highly conserved 14-3-3 protein family has risen to a position of importance in cell biology owing to its involvement in vital cellular processes, such as metabolism, protein trafficking, signal transduction, apoptosis and cell-cycle regulation. The 14-3-3 proteins are phospho-serine/phospho-threonine binding proteins that interact with a diverse array of binding partners. Because many 14-3-3 interactions are phosphorylation-dependent, 14-3-3 has been tightly integrated into the core phospho-regulatory pathways that are crucial for normal growth and development and that often become dysregulated in human disease states such as cancer. This review examines the recent advances that further elucidate the role of 14-3-3 proteins as integrators of diverse signaling cues that influence cell fate decisions and tumorigenesis.

Figure 1

Functions of 14-3-3 in proliferative, oncogenic, survival and stress signaling. (a) Under proliferative signaling conditions, 14-3-3 binding is required for the Ras-dependent heterodimerization of B-Raf and C-Raf and contributes to the full kinase activation of C-Raf. (b) Under oncogenic B-Raf signaling conditions, 14-3-3 mediates the constitutive heterodimerization of B-Raf and C-Raf and is required for the transforming potential of kinase-impaired B-Raf mutants (indicated by starburst shape). (c) Under survival signaling conditions, 14-3-3 binding inactivates numerous pro-apoptotic proteins, such as BAD, BAX and the FOXO transcription factors, by sequestering them from their sites of action such as the mitochondria and the nucleus. (d) Under stress signaling conditions, activated JNK disrupts 14-3-3 binding to several pro-apoptotic proteins by directly phosphorylating the 14-3-3 proteins themselves, thus, enabling the apoptosis regulators to localize to their site of action.

Figure 2

Functions of 14-3-3 in TORC1 signaling. (a) Under growth conditions, the AKT kinase is activated downstream of the insulin receptor (not depicted) and in turn activates TORC1 by phosphorylating TSC2 and PRAS40 on sites that mediate 14-3-3 binding and that relieve the inhibitory effects of these proteins. (b) AMPK is activated under conditions of low energy and inhibits TORC1 signaling by phosphorylating TSC2 and Raptor, thus, stimulating TSC2 activity and inhibiting Raptor function. AMPK-mediated phosphorylation of Raptor is required for the energy checkpoint induced by AMPK, and the sites that are phosphorylated mediate 14-3-3 binding. (c) REDD1 (DDIT4) expression is induced under hypoxic conditions and REDD1 inhibits TORC1 activity in a TSC2-dependent manner. REDD1 has been reported to reverse the inhibition of TSC2 by promoting the movement of 14-3-3 proteins from TSC2 to REDD1.

Figure 3

Functions of 14-3-3 in cytokinesis. (a) 14-3-3σ function is required for a mitotic translational switch. During mitosis, binding of 14-3-3σ to eIF4B and possibly to other factors involved in cap-dependent translation is required for the mitotic switch from cap-dependent to cap-independent translation. This translational switch is needed for the synthesis of key mitotic regulators required for proper mitotic exit and cytokinesis. mRNA shown as red line. Abbreviations: IRES, internal ribosome entry site. (b) 14-3-3 function in abscission. During mitosis, phosphorylation mediated by p38, GSK3 and PKCε generates 14-3-3 binding sites on PKCε. Binding of 14-3-3 activates PKCε and formation of the active PKCε–14-3-3 complex is needed to limit RhoA activity at the midbody, which in turn enables the actomyosin ring to dissociate during the final stages of abcission.

Figure 4

Functions of 14-3-3 in tumor-suppressor pathways. (a) The mammalian Hippo pathway transmits signals received at the cell surface, such as cell–cell contact, through the sequential activation of the Mst1/2–WW45 and Lats1/2–Mob kinase complexes. The Lats kinases phosphorylate YAP and TAZ on sites that mediate 14-3-3 binding, thus, inactivating the function of these transcriptional coactivators by means of their cytoplasmic retention. (b) β-catenin functions as a transcriptional coactivator in the Wnt signaling pathway. Cby antagonizes β-catenin signaling by preventing the interaction between β-catenin and the Tcf transcription factor enhancer and by mediating the formation of a stable β-catenin–Cby–14-3-3 tripartite complex that results in the nuclear export of β-catenin.