Identification of 14-3-3ζ as a Protein Kinase B/Akt Substrate

Powell, David W.; Rane, Madhavi J.; Chen, Qingdan; Singh, Saurabh; McLeish, Kenneth R.

doi:10.1074/jbc.m203167200

Cited by 87 publications

(61 citation statements)

References 23 publications

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“…Furthermore, the identification of 14-3-3 as an Aktbinding partner in CA1 SH immunoprecipitates was not entirely surprising. Akt substrates have been shown to associate with 14-3-3 in a phosphorylation-dependent manner, and we have demonstrated previously that 14-3-3 associates with Akt and is an Akt substrate (73). However, the role of 14-3-3 in the cellular response to SH and/or IH remains to be elucidated.…”

Section: Expression Of Constitutively Active Akt In Pc-12 Cells Inducmentioning

confidence: 95%

Akt-mediated Valosin-containing Protein 97 Phosphorylation Regulates Its Association with Ubiquitinated Proteins

Klein

Barati

et al. 2005

Journal of Biological Chemistry

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Hypoxia is a common environmental stress that influences signaling pathways and cell function. Previous studies from our laboratory have identified significant differences in cellular responses to sustained or intermittent hypoxia with the latter proving more cytotoxic. We hypothesized that differences in susceptibility of neurons to intermittent (IH) and sustained hypoxia (SH) are mediated by altered Akt signaling. SH, but not IH, induced a significant increase in Akt activation in rat CA1 hippocampal region extracts compared with room air controls. Most mammalian neurons are sensitive to hypoxia to a varying degree. However, the mechanisms underlying this heterogeneous sensitivity are not well understood. Heterotopic differences in hypoxic sensitivity are now well established in the brain during conditions of oxygen deprivation such as hypoxic ischemia and the oxidant stress that follows reperfusion or malonate-induced mitochondrial metabolic disruption (1-4). Previous studies from our laboratory have identified significant differences in the hypoxic susceptibility of the CA1 and CA3 hippocampal regions, with CA1 vulnerability being particularly prominent in response to intermittent mild hypoxic episodes (5-7). These findings suggest that the CA3 region is relatively resistant to hypoxia when compared with the CA1 region, and CA1 regional vulnerability to hypoxia varies depending on the mode, severity, and duration of the hypoxic insult (8 -10). The mechanisms underlying the greater susceptibility of the CA1 region to intermittent hypoxia (IH) 1 than to sustained hypoxia (SH) are unknown. We have recently shown in PC-12 cells that different signaling pathways are involved in sustained and intermittent hypoxia-induced cell death. Identifying these pathways may contribute to our understanding of differential brain susceptibility to sustained and intermittent hypoxia (11). In the present study, we found that in rat CA1, SH but not IH induces significant increase in Akt activation compared with room air (RA) control, suggesting that differences in Akt signaling maybe implicated in the differences in hypoxia sensitivity in IH versus SH. Proteomic analysis of Akt immunoprecipitates from RA, SH, and IH CA1 samples was performed to identify differences in the assembly of Akt-binding partners among different conditions. These studies demonstrated that SH but not IH increased expression and association of endoplasmic reticulum (ER)-proteasome interacting protein, velosin-containing protein 97 (VCP) with Akt, compared with RA-exposed animals. Additionally, VCP was identified as an Akt substrate in vitro and in vivo thereby potentially implicating the VCP-Akt complex in the regulation of protein quality control during SH.VCP is a member of the AAA (ATPases associated with various cellular activities) family and is divided into N (residues 1-187), D1 (residues 209 -460), D2 (residues 481-761), and C (residues 742-806) domains, and two linkers, N-D1 linker (residues 188 -208) and D1-D2 linker (residues 461-

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Section: Expression Of Constitutively Active Akt In Pc-12 Cells Inducmentioning

confidence: 95%

Akt-mediated Valosin-containing Protein 97 Phosphorylation Regulates Its Association with Ubiquitinated Proteins

Klein

Barati

et al. 2005

Journal of Biological Chemistry

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“…Two additional point mutants of 14-3-3 isoforms have been well characterized; mutation of serine 58, known to be phosphorylated by PKA or PKB/AKT1, to alanine (S58A) induces constitutive dimerization of 14-3-3, whereas mutation of this serine to aspartic acid (S58E) abrogates dimerization (31)(32)(33). However, as shown in Fig.…”

Section: Interaction Between Gpsm3 and 14-3-3 Family Membersmentioning

confidence: 99%

Regulation of the Subcellular Localization of the G-protein Subunit Regulator GPSM3 through Direct Association with 14-3-3 Protein

Giguère

Laroche

Oestreich

et al. 2012

Journal of Biological Chemistry

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Background: GPSM3, a guanine nucleotide dissociation inhibitor acting on G␣ i subunit family members, is both cytoplasmand nucleus-localized. Results: GPSM3 interacts directly with 14-3-3 through a phosphorylation-dependent mechanism. Conclusion: Interaction with 14-3-3 stabilizes a cytoplasmic pool of GPSM3. Significance: Our findings represent the first demonstration of post-translational modulation of GPSM3, a hematopoieticrestricted G-protein subunit regulator.

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“…1 Other targets of Akt include eNOS, caspase 9, Bad, 14−3−3 proteins, and p47 phox . 8,[19][20][21][22] Of these targets only Bad and FOXO were reported to be phosphorylated by Akt in mesangial cells. 7, 13 Recent work by Lewis et al using a proteomic approach to define targets of ERK phosphorylation suggested that a majority of substrates for specific kinases remain to be identified.…”

Section: Introductionmentioning

confidence: 99%

A Proteomic Screen Identified Stress-Induced Chaperone Proteins as Targets of Akt Phosphorylation in Mesangial Cells

et al. 2006

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The serine-threonine kinase Akt regulates mesangial cell apoptosis, proliferation, and hypertrophy. To define Akt signaling pathways in mesangial cells, we performed a functional proteomic screen for rat mesangial cell proteins phosphorylated by Akt. A group of chaperone proteins, heat shock protein (Hsp) 70, Hsp90α, Hsp90β, Glucose-regulated protein (Grp) Grp78, Grp94, and protein disulfide isomerase (PDI) were identified as potential Akt substrates by two techniques: (a) in vitro phosphorylation of mesangial cell lysate by recombinant active Akt followed by protein separation by SDS-PAGE or 2-DE and phosphoprotein identification by peptide mass fingerprinting using MALDI-MS, or (b) immunoblot analysis of proteins from PDGF-stimulated mesangial cells using an anti-Akt phospho-motif antibody. In vitro kinase reactions using recombinant proteins confirmed that Akt phosphorylates Hsp70, Hsp90α and β, Grp94, and PDI. Immunoprecipitation of Akt from mesangial cell lysate co-precipitated Grp78 and Hsp70. PDGF stimulation of mesangial cells caused an acidic shift in the isoelectric point of Hsp70, Hsp90, and PDI that was dependent on PI-3K activity for Hsp70 and Hsp90. The data suggest that Akt-mediated phosphorylation of stressinduced chaperones represents a mechanism for regulation of chaperone function during mesangial cell responses to physiologic and pathologic stimuli.

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Identification of 14-3-3ζ as a Protein Kinase B/Akt Substrate

Cited by 87 publications

References 23 publications

Akt-mediated Valosin-containing Protein 97 Phosphorylation Regulates Its Association with Ubiquitinated Proteins

Akt-mediated Valosin-containing Protein 97 Phosphorylation Regulates Its Association with Ubiquitinated Proteins

Regulation of the Subcellular Localization of the G-protein Subunit Regulator GPSM3 through Direct Association with 14-3-3 Protein

A Proteomic Screen Identified Stress-Induced Chaperone Proteins as Targets of Akt Phosphorylation in Mesangial Cells

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