14-3-3 Induced Intracellular Signaling
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14-3-3 Induced Intracellular Signaling
The 14-3-3 proteins are a family of conserved adaptor and scaffolding proteins expressed in all eukaryotic cells. It has evolved from a brain-specific protein to a family of ubiquitously expressed regulatory molecules of eukaryotic organisms. A striking feature of the 14-3-3 proteins is their ability to bind a multitude of functionally wide array of cellular proteins, including kinases, phosphatases, and transmembrane receptors. This plethora of interacting proteins allows 14-3-3 to play important roles in a wide range of vital regulatory processes, such as neuronal development, mitogenic signal transduction, apoptotic cell death, cell cycle control, cell growth control, and viral and bacterial pathogenesis. More than 50 signaling proteins have been reported as 14-3-3 ligands (Ref.1).

There are seven known mammalian 14-3-3 isoforms, (Beta, Epsilon, Gamma, Eta, Sigma, Tau and Zeta) named after their elution profile on reversed phase high-performance liquid chromatography. The species initially designated Alpha and Delta are actually the phosphorylated forms of Beta and Zeta. 14-3-3 proteins function as dimmers with each monomer able to bind a target. The primary function of the 14-3-3 proteins is to bind phosphoserine/threonine-containing motifs in a sequence-specific manner, e.g., RSxpSxP, mode-1 and RxxxpSxP, mode-2 (where pS represents phospho-serine), in a manner analogous to Src-homology 2 and phospho-tyrosine-binding domains that bind phosphotyrosine-containing motifs (Ref.2). 14-3-3 actions can be divided into four categories: inhibition, activation, structural stabilization, or translocation. Translocation may involve the intrinsic nuclear export signal in 14-3-3 and/or obstruction of a nuclear localization signal. 14-3-3 is abundant in the brain, but it is also present in almost all tissues, including testes, liver, and heart. Within a eukaryotic cell, 14-3-3 is largely found in the cytoplasmic compartment. However, 14-3-3 proteins can also be detected at the plasma membrane and in intracellular organelles such as the nucleus and the Golgi apparatus (Ref.3). 14-3-3-associated proteins include those involved in cell cycle control, such as CDC25, Wee1, p53, CDC2 (Cell Division Cycle-2), and CDK2 (Cyclin-Dependent Kinase-2); cellular signaling and stress responses, such as Raf1, IGFIR (Insulin-like Growth Factor-I Receptor), IRS1 (Insulin Receptor Substrate-1), PI3K(Phosphatidylinositol-3 Kinase), PLC (Phospholipase-C), PKC (Protein Kinase-C), Cbl, oncogene products BCR, polyomavirus MT (Middle Tumor antigen), MEKK1 (MAPK/ERK Kinase Kinase-1) and MEKK4, MLK2 (Mixed-Lineage Kinase-2), JNK (Jun N-terminal kinase), BAD (BCL2 Associated Death Promoter), and ASK1 (Apoptosis Signal-regulating Kinase-1); transcriptional regulation, such as FKHRL1 (Forkhead), DAF (Decay Accelerating Factor of complement), TAZ (Transcriptional co-activator with PDZ-binding motif) and histone deacetylase; and cytoskeletal proteins such as keratin K18 and Vimentin. The kinase activity of ASK1 (Apoptosis Signal-Regulating Kinase) is stimulated by TNF-Alpha(Tumor Necrosis Factor-Alpha) via members of the TRAF (TNF Receptor-Associated Factor) family, TRAF2 and by Fas ligation via the Daxx protein (Ref.4). ASK1 acts as a downstream target of TRAF2 in the JNK/SAPK (Stress-Activated Protein Kinase) pathway leading to transcriptional activation of heterodimer c-Jun and c-Fos. 14-3-3 binding regulates its partners through a variety of mechanisms, such as altering their catalytic activity, cellular localization, incorporation into protein complexes, or their susceptibility to proteases and phosphatases (Ref.5).

14-3-3 maintains Raf1 in an inactive state in the absence of activation signals but promotes Raf1 activation and stabilizes its active conformation when such signals are received (Ref.3). On activation by GRB2 (Growth Factor Receptor-Bound Protein-2), the small GTP binding protein Ras interacts directly with Raf1 and recruits Raf1 to the plasma membrane. Raf1 then phosphorylates the kinase MEK (MAPK/ERK Kinase), leading to stimulation of the ERK (Extracellular Signal-Regulated Kinase) signaling, which translocate to the nucleus and phosphorylate the transcription factor Elk1 involved in cell division, or they phosphorylate the RSK (p90 Ribosomal-S6 Kinase). Signaling via cell surface receptors initiates the mitogenic response of cells to many growth factors and is a frequent target for events involved in the process of tumorigenesis. RTK (Receptor Tyrosine Kinase) activation via growth factor stimulation or oncogenic mutation initiates several phosphorylation cascades, often involving the production of second messengers such as PIP2 (Phosphatidylinositol-3, 4-Bisphosphate), DAG (Diacylglycerol), etc. Activation of Akt/PKB (Protein Kinase-B) promotes cell survival and growth via phosphorylation of a number of substrates including PRAS (40-kDa Proline-Rich Akt Substrate), GSK-3Beta (Glycogen Synthase Kinase-3Beta), several mammalian homologs of the Caenorhabditis elegans DAF transcription factor, the anti-apoptotic protein BAD, YAP (Yes Associated Protein), Phosphodiesterase 3B, a Rab GTPase-activating protein, ATP Citrate Lyase, and most recently, TSC (Tuberous Sclerosis Complex). GSK-3Beta is a regulatory enzyme that phosphorylates several substrates including Tau in a complex containing Tubulin and 14-3-3 isoforms in normal brain. The phosphorylation of substrate by Akt result in the subsequent binding of the substrate to 14-3-3, which induce a change in the subcellular localization of a protein (Ref.6). Binding to 14-3-3 also retains phosphorylated YAP in the cytoplasm, resulting in its displacement from the nucleus where it functions as a co-activator of p73-mediated apoptosis. Signaling via Aktalso results in activation of p70S6K, which phosphorylates ribosomal protein S6K to promote protein synthesis and cell growth.

14-3-3 proteins are abundantly expressed in the brain and have been detected in the cerebrospinal fluid of patients with different neurological disorders. By their interaction with more than 100 binding partners, 14-3-3 proteins modulate the action of proteins that are involved in regulation of cell cycle arrest in response to DNA damage, cell cycle timing, intracellular trafficking, regulation of ion channels, and intracellular signaling in response to stress, mating pheromone in yeast, photoreceptor development and learning in Drosophila, cellular response to stress and survival factors in mammals, and the Ras/Raf signaling pathway in various organisms (Ref.5). Through protein-protein interactions, 14-3-3 carries out multiple functions. (a) In a broad sense, it can act as an allosteric cofactor to modulate the catalytic activity or conformational state of its effectors (b) 14-3-3 may function as steric regulator to prevent the interaction of its ligands with other cellular components, leading to altered intracellular localization or complex formation (c) The 14-3-3 dimmer can simultaneously bind two ligands, which may allow 14-3-3 to operate as an adaptor/scaffold protein to induce protein-protein associations. Syn-Alpha (Synuclein), one of the main components of Lewy bodies, also bind to 14-3-3 proteins, which share over 40% homology and reduces the activity of tyrosine hydroxylase (reduces dopamine synthesis) by binding to dephosphorylated tyrosine hydroxylase. 14-3-3 proteins continue to generate intense interest because of their roles in signal transduction pathways that control cell cycle checkpoints, MAPK activation, apoptosis and programs of gene expression. Despite this plethora of known binding proteins, in many cases the function of 14-3-3 in these interactions has remained obscure (Ref.6).