14-3-3 Proteins: diverse functions in cell proliferation and cancer progression

Abstract

The 14-3-3 proteins were the first phosphoserine/phosphothreonine-binding proteins to be discovered, a finding that provided the foundation for their prominent role in cell signaling. 14-3-3 family members interact with a wide spectrum of proteins including transcription factors, biosynthetic enzymes, cytoskeletal proteins, signaling molecules, apoptosis factors, and tumor suppressors. The interaction with 14-3-3 can have a profound effect on a target protein, altering its localization, stability, conformation, phosphorylation state, activity, and/or molecular interactions. Thus, by modulating the function of a diverse array of binding partners, 14-3-3 proteins have become key regulatory components in many vital cellular processes - processes that are crucial for normal growth and development and that often become dysregulated in human cancer. This review will examine the recent advances that further elucidate the role of 14-3-3 proteins in normal growth and cancer signaling with a particular emphasis on the signaling pathways that impact cell proliferation, cell migration, and epithelial-to-mesenchymal transition.

Fig. 1

The function of 14-3-3 in Raf kinase regulation. (A) In resting cells, a 14-3-3 dimer binds to phosphorylation sites found in the Raf N- and C-terminal regions, maintaining Raf in an inactive state in the cytosol. (B) In response to proliferative signals, 14-3-3 binding to the Raf C-terminal sites facilitates Raf dimerization in a Ras-dependent manner. (C) The N-terminal, negative regulatory 14-3-3 binding motif of C-Raf is frequently mutated in Noonan and LEOPARD syndromes. All mutationally-activated Raf proteins dimerize constitutively in a manner dependent on the Raf C-terminal 14-3-3 binding site.

Fig. 2

14-3-3 negatively regulates Hippo pathway signaling. (A) In the canonical Hippo pathway, Lats generates a phosphorylation-dependent 14-3-3 binding site on YAP/TAZ under conditions of high cell density. The binding of 14-3-3 sequesters YAP/TAZ in the cytosol. NPHP4 can complete with YAP/TAZ for Lats binding, thus blocking Lats-mediated phosphorylation of YAP/TAZ and 14-3-3 binding. (B) In non-canonical Hippo signaling, α-catenin forms a complex with 14-3-3-bound YAP under high cell density, thus stabilizing the 14-3-3/YAP interaction. Under low cell density conditions, PP2A dephosphorylates the 14-3-3 docking site on YAP, resulting in its nuclear import.

Fig. 3

14-3-3 interacts with proteins involved in actin remodeling. PKD phosphorylates SSH1L and cortactin, whereas Par1b and unknown kinase(s) phosphorylate IRSp53 to generate 14-3-3 binding motifs. 14-3-3 binding inhibits the function of these actin regulatory proteins.

Fig. 4

Involvement of 14-3-3 in EMT. (A) 14-3-3 binding to the TGFβ receptor I (TβR1) prevents TβR1 ubiquitination and degradation, thus increasing TGF/SMAD signaling. Elevated TGF/SMAD signaling upregulates the transcriptional repressor ZFHX1B, which in turn downregulates E-cadherin expression. (B) Binding of 14-3-3 to the EMT regulator Snail at pT177 positively regulates Snail/Ajuda repressor complexes, thus downregulating E-cadherin expression. (C) PKD-mediated phosphorylation of S11 negatively regulates Snail function by sequestering Snail in the cytosol through 14-3-3 binding.