Proteomic Identification of 14-3-3ζ as a Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Substrate: Role in Dimer Formation and Ligand Binding

Powell, David W.; Rane, Madhavi J.; Joughin, Brian A.; Kalmukova, Ralitsa; Hong, Jeong Ho; Tidor, Bruce; Dean, William L.; Pierce, William M.; Klein, Jon B.; Yaffe, Michael B.; McLeish, Kenneth R.

doi:10.1128/mcb.23.15.5376-5387.2003

Cited by 122 publications

(111 citation statements)

References 42 publications

(47 reference statements)

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“…In particular, one area of 14-3-3 biology that remains unclear concerns the role of monomeric 14-3-3 proteins. 14-3-3 molecules naturally form dimers, but phosphorylation of the dimer interface has been shown to promote the generation of 14-3-3 monomers (Hamaguchi et al, 2003;Powell et al, 2003;Woodcock et al, 2003). 14-3-3 monomers can bind target proteins, but how often monomers are formed in vivo and whether they have specific in vivo functions are unknown.…”

Section: Discussionmentioning

confidence: 99%

Unlocking the code of 14-3-3

Dougherty¹,

Morrison²

2004

Journal of Cell Science

436

384

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One of the most striking `rags to riches' stories in the protein world is that of 14-3-3, originally identified in 1967 as merely an abundant brain protein. The first clues that 14-3-3 would play an important role in cell biology came almost 25 years later when it was found to interact with various proto-oncogene proteins and signaling proteins. The subsequent identification of 14-3-3 as a phosphoserine/phosphothreonine-binding protein firmly established its importance in cell signaling. 14-3-3 family members are found in all eukaryotes – from plants to mammals – and more than 100 binding partners have been identified to date. The targets of 14-3-3 are found in all subcellular compartments and their functional diversity is overwhelming – they include transcription factors, biosynthetic enzymes, cytoskeletal proteins, signaling molecules, apoptosis factors and tumor suppressors. 14-3-3 binding can alter the localization, stability, phosphorylation state, activity and/or molecular interactions of a target protein. Recent studies now indicate that the serine/threonine protein phosphatases PP1 and PP2A are important regulators of 14-3-3 binding interactions, and demonstrate a role for 14-3-3 in controlling the translocation of certain proteins from the cytoplasmic and endoplasmic reticulum to the plasma membrane. New reports also link 14-3-3 to several neoplastic and neurological disorders, where it might contribute to the pathogenesis and progression of these diseases.

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Section: Discussionmentioning

confidence: 99%

Unlocking the code of 14-3-3

Dougherty¹,

Morrison²

2004

Journal of Cell Science

436

384

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“…14-3-3 was reported to interact with a number of components of cell signaling pathways, including protein kinases, phosphatases, and transcription factors (reviewed in reference 214). MK2-mediated phosphorylation of 14-3-3 on Ser58 was shown to compromise its binding activity (153), suggesting that MK2 may affect the regulation of several signaling molecules normally regulated by 14-3-3.…”

Section: Mk2 and -3 Subfamilymentioning

confidence: 99%

ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions

Roux

Blenis

2004

Microbiol Mol Biol Rev

2,159

1,861

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Conserved signaling pathways that activate the mitogen-activated protein kinases (MAPKs) are involved in relaying extracellular stimulations to intracellular responses. The MAPKs coordinately regulate cell proliferation, differentiation, motility, and survival, which are functions also known to be mediated by members of a growing family of MAPK-activated protein kinases (MKs; formerly known as MAPKAP kinases). The MKs are related serine/threonine kinases that respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs. There are currently 11 vertebrate MKs in five subfamilies based on primary sequence homology: the ribosomal S6 kinases, the mitogen- and stress-activated kinases, the MAPK-interacting kinases, MAPK-activated protein kinases 2 and 3, and MK5. In the last 5 years, several MK substrates have been identified, which has helped tremendously to identify the biological role of the members of this family. Together with data from the study of MK-knockout mice, the identities of the MK substrates indicate that they play important roles in diverse biological processes, including mRNA translation, cell proliferation and survival, and the nuclear genomic response to mitogens and cellular stresses. In this article, we review the existing data on the MKs and discuss their physiological functions based on recent discoveries

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“…Neutrophil lysate was prepared as previously described (22,23). In brief, 10 8 cells were lysed in 500 l of lysis buffer containing 2 M thiourea, 7 M urea, 65 mM CHAPS, 58 mM DTT, and 4.5% ampholytes (pH 3-10).…”

Section: Neutrophil Lysate Preparationmentioning

confidence: 99%

“…Lysates were cleared by centrifugation at 12,000 ϫ g for 20 min at 15°C. Before addition of exogenous p38 MAPK, lysate urea concentration was reduced to 1 M by size exclusion chromatography as previously described (22,23).…”

Section: Neutrophil Lysate Preparationmentioning

confidence: 99%

“…The only p38 MAPK substrates that have been identified in human neutrophils, however, are MAP-KAPK-2 and p47 phox (1,9,10,21). The goal of the present study was to identify p38 MAPK substrates in human neutrophils using a functional proteomic approach developed in our laboratory that combines in vitro phosphorylation of neutrophil lysate by recombinant kinase, separation of proteins by two-dimensional gel electrophoresis, and phosphoprotein identification by MALDI-TOF mass spectrometry (MALDI-TOF MS) (22,23). One of the proteins identified was myeloid-related protein-14 (MRP-14), a member of the S100 protein family of calcium binding proteins (24,25).…”

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confidence: 99%

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Myeloid-Related Protein-14 Is a p38 MAPK Substrate in Human Neutrophils

Lominadze

Rane

Merchant

et al. 2005

The Journal of Immunology

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The targets of the p38 MAPK pathway that mediate neutrophil functional responses are largely unknown. To identify p38 MAPK targets, a proteomic approach was applied in which recombinant active p38 MAPK and [32P]ATP were added to lysates from unstimulated human neutrophils. Proteins were separated by two-dimensional gel electrophoresis, and phosphoproteins were visualized by autoradiography and identified by MALDI-TOF. Myeloid-related protein-14 (MRP-14) was identified as a candidate p38 MAPK substrate. MRP-14 phosphorylation by p38 MAPK was confirmed by an in vitro kinase reaction using purified MRP-14/MRP-8 complexes. The site of MRP-14 phosphorylation by p38 MAPK was identified by tandem mass spectrometry and site-directed mutagenesis to be Thr113. MRP-14 phosphorylation by p38 MAPK in intact neutrophils was confirmed by [32P]orthophosphate loading, followed by fMLP stimulation in the presence and absence of a p38 MAPK inhibitor, SB203580. Confocal microscopy of Triton X-100 permeabilized neutrophils showed that a small amount of MRP-14 was associated with cortical F-actin in unstimulated cells. fMLP stimulation resulted in a p38 MAPK-dependent increase in MRP-14 staining at the base of lamellipodia. By immunoblot analysis, MRP-14 was present in plasma membrane/secretory vesicle fractions and gelatinase and specific granules, but not in azurophil granules. The amount of MRP-14 associated with plasma membrane/secretory vesicle and gelatinase granule fractions increased after fMLP stimulation in a p38 MAPK-dependent manner. Direct phosphorylation of the MRP-14/MRP-8 complex by p38 MAPK increased actin binding in vitro by 2-fold. These results indicate that MRP-14 is a potential mediator of p38 MAPK-dependent functional responses in human neutrophils.

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Proteomic Identification of 14-3-3ζ as a Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Substrate: Role in Dimer Formation and Ligand Binding

Cited by 122 publications

References 42 publications

Unlocking the code of 14-3-3

Unlocking the code of 14-3-3

ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions

Myeloid-Related Protein-14 Is a p38 MAPK Substrate in Human Neutrophils

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