Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD

Renganathan, Hemamalini; Vaidyanathan, Hema; Knapinska, Anna M.; Ramos, Joe W.

doi:10.1042/bj20050378

Cited by 103 publications

(107 citation statements)

References 17 publications

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“…When PEA15 is phosphorylated at both Ser 104 and Ser 116 , it blocks its interaction with ERK 1/2 both in vitro and in vivo, resulting in proliferation of cells that express high levels of PEA15 (Krueger et al, 2005). In another report, it has been shown that when PEA15 is phosphorylated at Ser104 it blocks ERK binding in vitro and in vivo, whereas it promotes binding to the proapoptotic protein FADD when it is phosphorylated at Ser116, resulting in inhibition of apoptosis (Renganathan et al, 2005). The role of the phosphorylation status of PEA15 in tumorigenicity needs further investigation.…”

Section: Discussionmentioning

confidence: 98%

Antitumor effect of E1A in ovarian cancer by cytoplasmic sequestration of activated ERK by PEA15

et al. 2005

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The adenovirus type 5 gene E1A is known to suppress tumorigenicity by transcriptionally downregulating HER-2/neu (HER2) or by inducing apoptosis. We show here that E1A also suppressed the tumorigenicity of the low-HER2-expressing ovarian cancer cell line OVCAR-3 by decreasing cell proliferation. We further found that the mechanism responsible for this reduced proliferation is the presence of PEA15 (phosphoprotein enriched in astrocytes), which is upregulated by E1A in ovarian cancer; PEA15 promotes translocation of ERK from the nucleus to the cytoplasm, leading to inhibition of ERK-dependent transcription and proliferation. Indeed, siRNA-mediated knockdown of PEA15 expression in OVCAR-3 stable E1A transfectants resulted in a nuclear accumulation of the active form of ERK, followed by an increase in Elk-1 activity, DNA synthesis, and anchorage-independent growth. Finally, PEA15 by itself suppressed colony formation in breast and ovarian cancer cell lines, in which E1A is known to have antitumor activity. We conclude that part of the antitumor effect of E1A in ovarian cancer results from cytoplasmic sequestration of the activated form of ERK by PEA15.

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Section: Discussionmentioning

confidence: 98%

Antitumor effect of E1A in ovarian cancer by cytoplasmic sequestration of activated ERK by PEA15

et al. 2005

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“…Although amplification of HER2 may be the best characterised genetic event in the development of these tumours, there are several genes included in these co-amplified regions that may also play a critical role in tumour development and response to therapy. For instance, the amplicon on chromosome 1q23 contains PEA15, which has a role in the development of other tumour types and interacts with the ERK/MAPK pathway, 46 whereas RAB22A on 20q13.2 belongs to the well-defined RAS oncogene family, which plays a crucial role in many types of cancer. 47 Although trastuzumab therapy is already changing the natural history of HER2 þ breast cancer, these tumours harbour multiple additional amplifications of genes that may either explain the primary resistance of specific subgroups of HER2 þ tumours to this therapy or could be tested as possible additional therapeutic targets for these tumours.…”

Section: Discussionmentioning

confidence: 99%

Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines

Arriola

Marchiò

Tan

et al. 2008

Laboratory Investigation

140

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HER2 and TOP2A are targets for the therapeutic agents trastuzumab and anthracyclines and are frequently amplified in breast cancers. The aims of this study were to provide a detailed molecular genetic analysis of the 17q12-q21 amplicon in breast cancers harbouring HER2/TOP2A co-amplification and to investigate additional recurrent co-amplifications in HER2/ TOP2A-co-amplified cancers. In total, 15 breast cancers with HER2 amplification, 10 of which also harboured TOP2A amplification, as defined by chromogenic in situ hybridisation, and 6 breast cancer cell lines known to be amplified for HER2 were subjected to high-resolution microarray-based comparative genomic hybridisation analysis. This revealed that the genomes of 12 cases were characterised by at least one localised region of clustered, relatively narrow peaks of amplification, with each cluster confined to a single chromosome arm (ie 'firestorm' pattern) and 3 cases displayed many narrow segments of duplication and deletion affecting the vast majority of chromosomes (ie 'sawtooth' pattern). The smallest region of amplification (SRA) on 17q12 in the whole series extended from 34.73 to 35.48 Mb, and encompassed HER2 but not TOP2A. In HER2/TOP2A-co-amplified samples, the SRA extended from 34.73 to 36.54 Mb, spanning a region of B1.8 Mb. Apart from HER2 and TOP2A, this region encompassed four additional genes whose expression levels as defined by quantitative real-time PCR are significantly higher in HER2/TOP2A-co-amplified vs HER2-amplified breast cancers: CASC3, CDC6, RARA and SMARCE1. Of the cell lines studied, SKBR3 and UACC812 showed HER2/TOP2A co-amplification. In conclusion, this is the first detailed genome-wide characterisation of HER2/TOP2A-amplified breast cancers; cell lines were identified that can be used to model these cancers in vitro. The 17q12 amplicon is complex and harbours multiple genes that may be associated with breast cancer development and progression, and potentially exploitable as therapeutic targets.

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“…Phosphorylation of these serines regulates PEA-15 binding to ERK and FADD (18). Therefore, we investigated whether phosphorylation of PEA-15 at these serines alters its ability to enhance ERK activation of RSK2.…”

Section: Pea-15 Enhances Erk-dependent Rsk2 Phosphorylation and Kinasementioning

confidence: 99%

ERK MAP kinase is targeted to RSK2 by the phosphoprotein PEA-15

Vaidyanathan

Opoku-Ansah

Pastorino

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The ERK pathway responds to extracellular stimuli and oncogenes by modulating cellular processes, including transcription, adhesion, survival, and proliferation. ERK has diverse substrates that carry out these functions. The processes that are modulated are determined in part by the substrates that ERK phosphorylates. We demonstrate that PEA-15 (phosphoprotein enriched in astrocytes, 15 kDa) targets ERK to RSK2 and thereby enhances RSK2 activation. PEA-15 independently bound ERK and RSK2 and increased ERK association with RSK2 in a concentration-dependent manner. PEA-15 increased RSK2 activity and CREB-mediated transcription, and this process was regulated by phosphorylation of PEA-15. Finally, phorbol ester stimulation of PEA-15-null lymphocytes resulted in impaired RSK2 activation that was rescued by exogenous PEA-15 expression. Therefore, PEA-15 functions as a scaffold to enhance ERK activation of RSK2, and this activity is regulated by phosphorylation. Thus, PEA-15 can integrate signal transduction to provide a specific physiological outcome from activation of the multipotent ERK MAP kinase pathway.signal transduction ͉ scaffold ͉ transcription ͉ lymphocytes T he ERK MAPK signaling cascade has been implicated in diverse physiological processes, including differentiation, proliferation, migration, and adhesion (1). This ability to impact several processes is partly because ERK recognizes an array of substrates both cytoplasmic and nuclear to elicit specific responses. However, how such a multipotent pathway achieves specificity of response is an ongoing problem in understanding ERK function. ERK interaction with scaffolding proteins, regulation of the duration of the ERK signal, and restriction of ERK to specialized subcellular compartments have all been suggested to contribute to this specificity (2-4). However, thus far, the mammalian scaffolding proteins for ERK such as KSR are known to act only upstream of ERK to enhance ERK activation without directing ERK to a particular substrate (5, 6). PEA-15 (phosphoprotein enriched in astrocytes, 15 kDa) is a small death effector domain protein that binds ERK and RSK2 and sequesters them in the cytoplasm (7,8). RSK2 is a substrate of ERK and a kinase that can activate transcription, regulate apoptosis, and control cancer cell proliferation (9-11). Therefore, we investigated whether PEA-15 influences ERK activation of RSK2. We show that increasing expression of PEA-15 enhances ERK binding to RSK2, ERK phosphorylation of RSK2, and RSK2 activity. Moreover, genetic deletion of PEA-15 substantially abrogates ERK activation of RSK2 in astrocytes and lymphocytes. RSK2 activation can be rescued by ectopic expression of PEA-15 in these cells. Thus, PEA-15 functions as a scaffold to enhance ERK binding and phosphorylation of RSK2. It does not affect the phosphorylation of other ERK substrates, such as stathmin and Mnk1. This work provides a model to understand how scaffold proteins can integrate signal transduction and provide specificity in MAP kinase signaling.

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Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD

Cited by 103 publications

References 17 publications

Antitumor effect of E1A in ovarian cancer by cytoplasmic sequestration of activated ERK by PEA15

Antitumor effect of E1A in ovarian cancer by cytoplasmic sequestration of activated ERK by PEA15

Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines

ERK MAP kinase is targeted to RSK2 by the phosphoprotein PEA-15

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