Siah Proteins Induce the Epidermal Growth Factor-dependent Degradation of Phospholipase Cϵ

Yun, Sanguk; Möller, Andreas; Chae, Suhn-Kee; Hong, Won-Pyo; Bae, Young Ju; Bowtell, David D.L.; Ryu, Sung Ho; Suh, Pann‐Ghill

doi:10.1074/jbc.m705874200

Cited by 16 publications

(15 citation statements)

References 38 publications

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“…Polyubiquitination of proteins is usually achieved by substrate-specific E3 ubiquitin ligases. SIAH2 is an E3 ligase, which is activated by the Ras signaling pathway and Src kinase (56,70). When we overexpressed SIAH2 in MCF-10A cells, it alone downregulated endogenous C/EBP␦ (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Identification of a Src Tyrosine Kinase/SIAH2 E3 Ubiquitin Ligase Pathway That Regulates C/EBPδ Expression and Contributes to Transformation of Breast Tumor Cells

Sarkar

Sharan

Wang

et al. 2012

Molecular and Cellular Biology

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The transcription factor CCAAT/enhancer-binding protein delta (C/EBP␦, CEBPD) is a tumor suppressor that is downregulated during breast cancer progression but may also promote metastasis. Here, we have investigated the mechanism(s) regulating C/EBP␦ expression and its role in human breast cancer cells. We describe a novel pathway by which the tyrosine kinase Src downregulates C/EBP␦ through the SIAH2 E3 ubiquitin ligase. Src phosphorylates SIAH2 in vitro and leads to tyrosine phosphorylation and activation of SIAH2 in breast tumor cell lines. SIAH2 interacts with C/EBP␦, but not C/EBP␤, and promotes its polyubiquitination and proteasomal degradation. Src/SIAH2-mediated inhibition of C/EBP␦ expression supports elevated cyclin D1 levels, phosphorylation of retinoblastoma protein (Rb), motility, invasive properties, and survival of transformed cells. Pharmacological inhibition of Src family kinases by SKI-606 (bosutinib) induces C/EBP␦ expression in an SIAH2-dependent manner, which is necessary for "therapeutic" responses to SKI-606 in vitro. Ectopic expression of degradation-resistant mutants of C/EBP␦, which do not interact with SIAH2 and/or cannot be polyubiquitinated, prevents full transformation of MCF-10A cells by activated Src (Src truncated at amino acid 531 [Src-531]) in vitro. These data reveal that C/EBP␦ expression can be regulated at the protein level by oncogenic Src kinase signals through SIAH2, thus contributing to breast epithelial cell transformation.

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Section: Resultsmentioning

confidence: 99%

“…The highly homologous protein SIAH1 can be phosphorylated on at least three tyrosines. Mutation of all three tyrosines or the pharmacological Src family tyrosine kinase inhibitor PP2 blocks SIAH1-mediated ubiquitination of its target phospholipase C (PLC) (70). Therefore, we next assessed the phosphorylation status of SIAH2.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Src Tyrosine Kinase/SIAH2 E3 Ubiquitin Ligase Pathway That Regulates C/EBPδ Expression and Contributes to Transformation of Breast Tumor Cells

Sarkar

Sharan

Wang

et al. 2012

Molecular and Cellular Biology

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show abstract

“…In addition, it was evidenced that PLC-ε plays a role in agonist-dependent proliferation. PLC-ε induced PDGF-dependent cell growth in BaF3 cells overexpressing PDGF receptor (198) or EGF-dependent cell growth in HEK293 cells or MEF cells (197,206). A recent report indicates that thrombin-dependent astrocyte proliferation is mediated by PLC-ε (207).…”

Section: Plc-ε Is Involved In Cell Proliferationmentioning

confidence: 99%

“…The CDC25 domain of PLC-ε functions as a GEF for Rap1A and helps persistent Rap1A-dependent PLC-ε activation (191). RA2 domain also mediates the interaction with ubiquitin E3 ligase Siah, which leads to growth factor-dependent degradation of PLC-ε (197).…”

Section: Plc-ε Isozymementioning

confidence: 99%

Multiple roles of phosphoinositide-specific phospholipase C isozymes

Suh¹,

Park²,

Manzoli³

et al. 2008

BMB Reports

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450

482

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“…In line with this assumption, a previous report showed that Siah-1 is Tyr-phosphorylated at multiple residues by Src, which modulates Siah-1 activity. 24 Taken together, our data suggest that Src inhibits HIPK2 degradation by counteracting the function of the ubiquitin ligase Siah-1.…”

Section: Src Interferes With Hipk2 Degradation Mediated By the Ubiquimentioning

confidence: 66%

Src kinase modulates the apoptotic p53 pathway by altering HIPK2 localization

et al. 2013

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Siah Proteins Induce the Epidermal Growth Factor-dependent Degradation of Phospholipase Cϵ

Cited by 16 publications

References 38 publications

Identification of a Src Tyrosine Kinase/SIAH2 E3 Ubiquitin Ligase Pathway That Regulates C/EBPδ Expression and Contributes to Transformation of Breast Tumor Cells

Identification of a Src Tyrosine Kinase/SIAH2 E3 Ubiquitin Ligase Pathway That Regulates C/EBPδ Expression and Contributes to Transformation of Breast Tumor Cells

Multiple roles of phosphoinositide-specific phospholipase C isozymes

Src kinase modulates the apoptotic p53 pathway by altering HIPK2 localization

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