14-3-3 Proteins Are Required for Maintenance of Raf-1 Phosphorylation and Kinase Activity

Thorson, John; Yu, Lily W.K.; Hsu, Alice L.; Shih, Neng Yao; Graves, Paul R.; Tanner, J. William; Allen, Paul M.; Piwnica‐Worms, Helen; Shaw, Andréy S.

doi:10.1128/mcb.18.9.5229

Cited by 205 publications

(186 citation statements)

References 71 publications

(72 reference statements)

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“…mean, n=6) are given relative to a control sample (100%) that was incubated without peptide. The results have been pooled from three experiments The e ect of PS/Ca is also quite distinct from the two documented e ects that detergents have on Raf-1: RIPA bu er displaces 14-3-3 from Raf-1 without a ecting kinase activity (Michaud et al, 1995), whereas Empigen-BB displaces 14-3-3 and inactivates Raf-1 (Thorson et al, 1998). Clearly the e ect of PS/ Ca mimics neither of these.…”

Section: Discussionmentioning

confidence: 92%

Interactions of c-Raf-1 with phosphatidylserine and 14-3-3

et al. 1999

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Section: Discussionmentioning

confidence: 92%

Interactions of c-Raf-1 with phosphatidylserine and 14-3-3

et al. 1999

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“…Both mutants lack serines-43 and -259, and serine-621 is the only site that becomes phosphorylated in response to PKA activation [81,82]. However, other studies correlated serine-621 phosphorylation and 14-3-3 binding with an increase in activity [85]. The reason for this discrepancy is unclear at present.…”

Section: Making Connections : 14-3-3 Is At the Hubmentioning

confidence: 82%

Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions

Kölch

2000

Biochemical Journal

1,050

118

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The Ras\Raf\MEK (mitogen-activated protein kinase\ERK kinase)\ERK (extracellular-signal-regulated kinase) pathway is at the heart of signalling networks that govern proliferation, differentiation and cell survival. Although the basic regulatory steps have been elucidated, many features of this pathway are only beginning to emerge. This review focuses on the role of protein-protein interactions in the regulation of this pathway, INTRODUCTIONThe mitogen-activated protein kinase (MAPK) pathway is one of the primordial signalling systems that Nature has used in several permutations to accomplish an amazing variety of tasks. It exists in all eukaryotes, and controls such fundamental cellular processes as proliferation, differentiation, survival and apoptosis. The basic arrangement includes a G-protein working upstream of a core module consisting of three kinases : a MAPK kinase kinase (MAPKKK) that phosphorylates and activates a MAPK kinase (MAPKK), which in turn activates MAPK ( Figure 1). This set-up provides not only for signal amplification, but, maybe even more importantly, for additional regulatory interfaces that allow the kinetics, duration and amplitude of the activity to be precisely tuned. At present we can distinguish six MAPK modules, which share structurally related components, but seem to mediate specific biological responses. For recent reviews on MAPK pathways, the reader is referred to references [1][2][3]. Here we will focus on the regulation of the ERK (extracellular-signal-regulated kinase) pathway, which features Ras as G-protein, Raf as MAPKKK, MEK (MAPK\ERK kinase) as MAPKK and ERK as MAPK.Despite enjoying a decade in the limelight of scientific interest and revealing a plethora of new insights into the circuitry of signalling pathways in general, this pathway still holds many secrets. These pertain mainly to the regulation of Raf, and to a deeper understanding of how specific biological responses are encoded by spatial and temporal changes in the activity and subcellular distribution of the pathway components, and how these fluctuations are orchestrated at the molecular level. Work from many laboratories has highlighted protein-protein interactions as powerful means of co-ordinating signalling processes, most strikingly exemplified by the assembly of multi-protein signalling complexes on activated receptors, or of transcriptionfactor complexes on gene promoters. However, it is becoming Abbreviations used : Bcr, Breakpoint cluster region ; BXB, isolated Raf-1 kinase domain ; CNK, connector-enhancer of KSR ; CK2, casein kinase 2 ; CRD, cysteine-rich domain ; DEF, docking site for ERK, FxFP ; DLK, dual leucine-zipper-bearing kinase ; ERK, extracellular-signal-regulated kinase ; Hsp, heat-shock protein ; KIM, kinase interaction motif ; IκB, inhibitor of NF-κB ; JNK, c-Jun N-terminal kinase ; KSR, kinase suppressor of Ras ; MAPK, mitogen-activated protein kinase ; MAPKK, MAPK kinase ; MAPKKK, MAPK kinase kinase ; MEK, MAPK/ERK kinase ; MEKK, MEK kinase ; MP1, MEK partner 1 ; MUK, MAPK upstream kin...

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“…51 The 14-3-3e protein encoded by the YWHAE gene binds to phosphoserine-containing proteins and mediates signal transduction. For example, 14-3-3 binding is required for the stabilization of active RAF-1 52 and CDC25-mediated cell cycle control, 53 whereas its interaction with BAD and BAX prevents their proapoptotic release to mitochondrial membrane. 54,55 The PRKDC protein belongs to the PI3-K related kinase family and represents a key complex for DNA repair.…”

Section: Discussionmentioning

confidence: 99%

Identification of new genes associated with breast cancer progression by gene expression analysis of predefined sets of neoplastic tissues

Cimino

Fuso

Sfiligoi

et al. 2008

Intl Journal of Cancer

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Gene expression profiles were studied by microarray analysis in 2 sets of archival breast cancer tissues from patients with distinct clinical outcome. Seventy-seven differentially expressed genes were identified when comparing 30 cases with relapse and 30 cases without relapse within 72 months from surgery. These genes had a specific ontological distribution and some of them have been linked to breast cancer in previous studies: AIB1, the two keratin genes KRT5 and KRT15, RAF1, WIF1 and MSH6. Seven out of 77 differentially expressed genes were selected and analyzed by qRT-PCR in 127 cases of breast cancer. The expression levels of 6 upregulated genes (CKMT1B, DDX21, PRKDC, PTPN1, SLPI, YWHAE) showed a significant association to both disease-free and overall survival. Multivariate analysis using the significant factors (i.e., estrogen receptor and lymph node status) as covariates confirmed the association with survival. There was no correlation between the expression level of these genes and other clinical parameters. In contrast, SERPINA3, the only downregulated gene examined, was not associated with survival, but correlated with steroid receptor status. An indirect validation of our genes was provided by calculating their association with survival in 3 publicly available microarray datasets. CKMT1B expression was an independent prognostic marker in all 3 datasets, whereas other genes confirmed their association with disease-free survival in at least 1 dataset. This work provides a novel set of genes that could be used as independent prognostic markers and potential drug targets for breast cancer. ' 2008 Wiley-Liss, Inc.Key words: breast cancer; gene expression; microarray analysis; prognosticThe heterogeneous nature of breast cancer reflects the complexity of the molecular alterations that underlie the development and progression of this disease and poses serious problems to clinical management, also due to the lack of reliable pathological or molecular markers.There are a number of major open questions, such as the evaluation of risk of distant metastasis in cases characterized by the presence of favorable indicators (negative axillary lymph nodes and/or positive estrogen receptors), the prediction of response to chemotherapy and/or antiestrogenic therapy and the prediction of metastases sites for high-risk cancers. Moreover, the principal molecular alterations leading to aggressive clinical behavior, representing potential therapeutic targets, still need to be identified in addition to the well-known factor ERBB2 and the estrogen receptor pathways.Molecular profiling using DNA microarrays have provided sound advancements in this field. The expression profile of gene clusters were useful in classifying breast tumors in biological subgroups with clinical relevance, 1 or in low-versus high-risk classes for relapse, 2-5 or to predict responsiveness to either hormonal-or chemo-therapy. 6,7 In a well-known study, van't Veer et al. addressed the risk of relapse in node-negative patients, 2 one of the most clinicall...

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14-3-3 Proteins Are Required for Maintenance of Raf-1 Phosphorylation and Kinase Activity

Cited by 205 publications

References 71 publications

Interactions of c-Raf-1 with phosphatidylserine and 14-3-3

Interactions of c-Raf-1 with phosphatidylserine and 14-3-3

Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions

Identification of new genes associated with breast cancer progression by gene expression analysis of predefined sets of neoplastic tissues

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