How do 14‐3‐3 proteins work? – Gatekeeper phosphorylation and the molecular anvil hypothesis

Yaffe, Michael B.

doi:10.1016/s0014-5793(01)03288-4

Cited by 618 publications

(580 citation statements)

References 79 publications

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“…They bind to specific phosphoserine-or phosphothreonine-containing motifs within target proteins that generally match with either RxxpSxP (mode I) or RxxxpSxP (mode II) (Muslin et al, 1996). Their rigid structure and dimeric nature allow them to act as intra-and intermolecular adapters and to alter specific properties of their target proteins (Yaffe, 2002). Mutational analyses identified two conserved 14-3-3 interacting motifs in HDAC5 and HDAC9 (centered on Ser 259 and Ser 497 in HDAC5 and Ser 220 and Ser 451 in HDAC9).…”

Section: Structure Of Class Iia Hdacs: the N-terminal Adapter Domainmentioning

confidence: 99%

Class IIa histone deacetylases: regulating the regulators

2007

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Section: Structure Of Class Iia Hdacs: the N-terminal Adapter Domainmentioning

confidence: 99%

Class IIa histone deacetylases: regulating the regulators

2007

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“…14-3-3 adapter proteins are known to function as dimers that link their binding partners (Aitken et al, 2002;Yaffe, 2002). APC binds to 14-3-3 ( Fig.…”

Section: α3*nachrs Link To Apc Via 14-3-3 Adapter Proteinmentioning

confidence: 99%

Adenomatous polyposis coli plays a key role, in vivo, in coordinating assembly of the neuronal nicotinic postsynaptic complex

Rosenberg

Yang

Giovanni

et al. 2008

Molecular and Cellular Neuroscience

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The neuronal nicotinic synapse plays a central role in normal cognitive and autonomic function. Molecular mechanisms that direct the assembly of this synapse remain poorly defined, however. We show here that adenomatous polyposis coli (APC) organizes a multi-molecular complex that is essential for targeting α3*nAChRs to synapses. APC interaction with microtubule plus-end binding protein EB1 is required for α3*nAChR surface membrane insertion and stabilization. APC brings together EB1, the key cytoskeletal regulators macrophin and IQGAP1, and 14-3-3 adapter protein at nicotinic synapses. 14-3-3, in turn, links the α3-subunit to APC. This multi-molecular APC complex stabilizes the local microtubule and F-actin cytoskeleton and links postsynaptic components to the cytoskeleton-essential functions for controlling the molecular composition and stability of synapses. This work identifies macrophin, IQGAP1 and 14-3-3 as novel nicotinic synapse components and defines a new role for APC as an in vivo coordinator of nicotinic postsynaptic assembly in vertebrate neurons.

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“…As S729 of B-Raf is a known 14-3-3 recruitment site (MacNicol et al, 2000), we performed alanine substitutions of S365 and S729, singly and in combination. Many 14-3-3 client proteins possess more than one 14-3-3 binding site and in this case, it is necessary to eliminate both binding sites to observe an altered stoichiometry of the 14-3-3/client protein complex (Yaffe, 2002). Indeed, mutation of both sites was required to achieve a drastic reduction of the B-Raf/ 14-3-3 interaction ( Figure 3a).…”

Section: Regulation Of B-raf Signalling T Brummer Et Almentioning

confidence: 99%

Functional analysis of the regulatory requirements of B-Raf and the B-RafV600E oncoprotein

et al. 2006

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The BRAF V600E mutation is found in approximately 6% of human cancers and mimics the phosphorylation of the kinase domain activation segment. In wild-type B-Raf (B-Raf wt ), activation segment phosphorylation is thought to cooperate with negative charges within the N-region for full activation. In contrast to Raf-1, the N-region of B-Raf is constitutively negatively charged owing to the presence of residues D447/D448 and the phosphorylation of S446. Therefore, it has been suggested that this hallmark predisposes B-Raf for oncogenic activation. In this study, we demonstrate that neutralizing mutations of these residues (in particular S446 and S447), or uncoupling of B-Raf from Ras-guanine 5 0 -triphosphate (GTP), strongly reduce the biological activity of B-Raf in a PC12 cell differentiation assay. We also confirm that S365 is a 14-3-3 binding site, and determine that mutation of this residue rescues the impaired biological activity of B-Raf proteins with a neutralized N-region, suggesting that the N-region opposes a 14-3-3-mediated transition into an inactive conformation. However, in the case of B-Raf V600E , although complete N-region neutralization resulted in a 2.5-fold reduction in kinase activity in vitro, this oncoprotein strongly induced PC12 differentiation or transformation and epithelial-mesenchymal transition of MCF-10A cells regardless of its N-region charge. Furthermore, the biological activity of B-Raf V600E was independent of its ability to bind Ras-GTP. Our analysis identifies important regulatory differences between B-Raf wt and B-Raf V600E and suggests that B-Raf V600E cannot be inhibited by strategies aimed at blocking S446 phosphorylation or Ras activation. Keywords: Ras; 14-3-3 proteins; b-Catenin; E-cadherin; mammary epithelial cells IntroductionThe Ras/Raf/mitogen-activated/extracellular-regulated kinase (MEK)/extracellular signal regulated kinase (ERK) pathway plays a pivotal role in control of proliferation and differentiation and, owing to its role as a gatekeeper of this pathway, Raf appears an attractive therapeutic target (O'Neill and Kolch, 2004;Wilhelm et al., 2004). The Raf-kinase family comprises the A-Raf, B-Raf and Raf-1 isoforms in vertebrates as well as D-Raf and LIN-45 in Drosophila and Caenorhabditis, respectively. B-Raf, the major ERK activator in vertebrates, is required for the maintenance of basal ERK activity and displays the most potent transforming activity (Papin et al., 1998;Brummer et al., 2002;Mercer and Pritchard, 2003). All isoforms share three highly conserved regions (CRs; Figure 1a): the N-terminal CR1 contains the Ras-guanine 5 0 -triphosphate (GTP)-binding domain (RBD), which initiates the interaction with Ras-GTP through a conserved arginine residue (R188 in B-Raf) that is required for the recruitment and activation of Raf at the plasma membrane. Consequently, mutation of this residue prevents Ras/Raf interaction and renders D-Raf, B-Raf and Raf-1 unresponsive to most extracellular signals (Hou et al., 1995;Marais et al., 1997;Brummer et al., 2002). The ...

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How do 14‐3‐3 proteins work? – Gatekeeper phosphorylation and the molecular anvil hypothesis

Abstract: 14-3-3 proteins were the first

Cited by 618 publications

References 79 publications

Class IIa histone deacetylases: regulating the regulators

Class IIa histone deacetylases: regulating the regulators

Adenomatous polyposis coli plays a key role, in vivo, in coordinating assembly of the neuronal nicotinic postsynaptic complex

Functional analysis of the regulatory requirements of B-Raf and the B-RafV600E oncoprotein

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