The CUL7/F-box and WD Repeat Domain Containing 8 (CUL7/Fbxw8) Ubiquitin Ligase Promotes Degradation of Hematopoietic Progenitor Kinase 1 (original) (raw)
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ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer
F-box and WD repeat domain-containing 7 (FBW7) is the substrate recognition component of the Skp1-Cul1-Fbox (SCF) ubiquitin ligase complex and functions as a major tumor suppressor by targeting various oncoproteins for degradation. Genomic deletion or mutation of FBW7 has frequently been identified in many human cancers but not in pancreatic ductal adenocarcinoma. Thus it is important to know how the tumor suppressive function of FBW7 is impaired in pancreatic cancer. In this study, we first observed that low FBW7 expression correlated significantly with ERK activation in pancreatic cancer clinical samples, primarily due to KRAS mutations in pancreatic cancer. We further showed that ERK directly interacted with FBW7 and phosphorylated FBW7 at Thr205, which sequentially promoted FBW7 ubiquitination and proteasomal degradation. Furthermore, the phospho-deficient T205A FBW7 mutant is resistant to ERK activation and could significantly suppress pancreatic cancer cell proliferation and tumorigenesis. These results collectively demonstrate how the oncogenic KRAS mutation inhibits the tumor suppressor FBW7, thus revealing an important function of KRAS mutations in promoting pancreatic cancer progression.
Molecular Cell, 2008
Recent genetic studies have documented a pivotal growth-regulatory role played by the Cullin 7 (CUL7) E3 ubiquitin ligase complex containing the Fbw8-substrate-targeting subunit, Skp1, and the ROC1 RING finger protein. In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends onmammalian target of rapamycin and the p70 S6 kinase activities. Interestingly, while embryonic fibroblasts of Cul7 −/− mice were found to accumulate IRS-1 and exhibit increased activation of IRS-1's downstream Akt and MEK/ERK pathways, these null cells grew poorly and displayed phenotypes reminiscent of those associated with oncogene-induced senescence. Taken together, our findings demonstrate a key role for the CUL7 E3 in targeting IRS-1 for degradation, a process that may contribute to the regulation of cellular senescence.
The Journal of biological chemistry, 2015
The human Inhibitor of Bruton's tyrosine kinase isoform α (IBtkα) is a BTB protein encoded by the IBTK gene, which maps to chromosomal locus 6q14.1, a mutational hot spot in lymphoproliferative disorders. Here, we demonstrate that IBtkα forms a CRL3(IBTK) complex promoting its self-ubiquitylation. We identified the tumor suppressor Pdcd4 as IBtkα interactor and ubiquitylation substrate of CRL3(IBTK) for proteasomal degradation. Serum-induced degradation of Pdcd4 required both IBtkα and Cul3, indicating that CRL3(IBTK) regulated the Pdcd4 stability in serum signalling. By promoting Pdcd4 degradation, IBtkα counteracted the suppressive effect of Pdcd4 on translation of reporter luciferase mRNAs with stem-loop structured or unstructured 5'UTR. IBtkα depletion by RNAi caused Pdcd4 accumulation, and decreased the translation of Bcl-xL mRNA, a well-known target of Pdcd4 repression. By characterizing CRL3(IBTK) as a novel ubiquitin ligase, this study provides new insights into regu...
AURKA is one of the downstream targets of MAPK1/ERK2 in pancreatic cancer
Oncogene, 2006
DUSP6/MKP-3, a specific inhibitor of MAPK1/ERK2, frequently loses its expression in primary pancreatic cancer tissues. This evidence suggests that constitutive activation of MAPK1 synergistically induced by frequent mutation of KRAS2 and the loss of function of DUSP6 plays key roles in pancreatic carcinogenesis and progression. By profiling of gene expressions associated with downregulation of MAPK1 induced by exogenous overexpression of DUSP6 in pancreatic cancer cells, we found that AURKA/STK15, the gene encoding Aurora-A kinase, which plays key roles in cellular mitosis, was among the downregulated genes along with its related genes, which included AURKB, TPX2 and CENPA. An association of expression and promoter activity of AURKA with MAPK activity was verified. Knockdown of ETS2 resulted in a reduction of AURKA expression. These results indicate that AURKA is a direct target of the MAPK pathway and that its overexpression in pancreatic cancer is induced by hyperactivation of the pathway, at least via ETS2.
Journal of Biological Chemistry, 2003
Sustained extracellular signal-regulated kinase 1/2 (ERK1/2) activation does not always correlate with its upstream Ras-Raf-mitogen-activated protein kinase kinase 1/2 (MKK1/2) signal cascade in cancer cells, and the mechanism remains elusive. Here we report a novel mechanism by which sustained ERK1/2 activation is established. We demonstrate that Pb(II), a carcinogenic metal, persistently induces ERK1/2 activity in CL3 human lung cancer cells and that Ras-Raf-MKK1/2 signaling cannot fully account for such activation. It is intriguing that Pb(II) treatment reduces mitogenactivated protein kinase phosphatase 1 (MKP-1) protein levels in time-and dose-dependent manners, which correlates with sustained ERK1/2 activation, and that Pb(II) also induces mRNA and de novo protein synthesis of MKP-1. In Pb(II)-treated cells, MKP-1 is polyubiquitinated, and proteasome inhibitors markedly alleviate the ubiquitination and degradation of MKP-1. Inhibiting the Pb(II)-induced ERK1/2 activation by PD98059 greatly suppresses MKP-1 ubiquitination and degradation. It is remarkable that constitutive activation of MKK1/2 triggers endogenous MKP-1 ubiquitination and degradation in various mammalian cell lines. Furthermore, expression of functional MKP-1 decreases ERK1/2 activation and the c-Fos protein level and enhances cytotoxicity under Pb(II) exposure. Taken together, these results demonstrate that activated ERK1/2 can trigger MKP-1 degradation via the ubiquitin-proteasome pathway, thus facilitating long-term activation of ERK1/2 against cytotoxicity.
Journal of Biological Chemistry, 2008
Spy1A is a cyclin-like protein required for progression through the G 1 /S phase of the cell cycle. Elevated Spy1A protein levels have been implicated in tumorigenesis and are attributed to overriding the DNA damage response and enhancing cell proliferation. Understanding how Spy1A is produced and degraded is essential in resolving how it contributes to normal and abnormal growth processes. Herein, we demonstrate that Spy1A is degraded in a cell cycle-dependent manner during mitosis via the ubiquitin-proteasome system. We have resolved the E3 ligase and essential phosphorylation sites mediating Spy1A degradation. Furthermore, we have determined that non-degradable forms of Spy1A do not trigger cell cycle arrest but, rather, contribute to uncontrolled cell growth. Further investigation into the regulation of Spy1A may reveal novel strategies for understanding the etiology and progression of specific growth disorders.
MAPK SIGNALLING PATHWAY: ROLE IN CANCER PATHOGENESIS
Cancer is one of the prime causes of death presently. In normal cells, the firmly regulated pathway relays extracellular signals from the cell membrane to nucleus through a cascade of phosphorylation events. The Mitogen-Activated Protein Kinase (MAPK) cascades are among the most thoroughly studied signal transduction systems and have been proven to participate in a diverse array of cellular programs consisting of cell differentiation, cell movement, cell division and cell death. Constitutive activation of the MAPK cascade is associated with the carcinogenesis and melanoma development because of activating mutations within the B-RAF and RAS genes or other genetic or epigenetic modifications in their components or upstream activation of cell-surface receptors (e. g., EGFR and Flt-3) and chimeric chromosomal translocations (e. g. BCR-ABL) leading to elevated signaling activity eliciting cellular proliferation, invasion, metastasis, migration, survival and angiogenesis. Even in the absence of apparent genetic mutations, MAPK pathway has been stated to be activated in over 50% of Acute Myelogenous Leukemia (AML) and acute lymphocytic leukemia. In this brief review, we are about to outline the current advances in understanding the regulation of Mitogen-activated protein kinase signaling system and how can we generate specificity.
Molecular Cancer, 2013
Background The novel Akt inhibitor, API-1, induces apoptosis through undefined mechanisms. The current study focuses on revealing the mechanisms by which API-1 induces apoptosis. Results API-1 rapidly and potently reduced the levels of Mcl-1 primarily in API-1-senstive lung cancer cell lines. Ectopic expression of Mcl-1 protected cells from induction of apoptosis by API-1. API-1 treatment decreased the half-life of Mcl-1, whereas inhibition of the proteasome with MG132 rescued Mcl-1 reduction induced by API-1. API-1 decreased Mcl-1 levels accompanied with a rapid increase in Mcl-1 phosphorylation (S159/T163). Moreover, inhibition of GSK3 inhibited Mcl-1 phosphorylation and reduction induced by API-1 and antagonized the effect of API-1 on induction of apoptosis. Knockdown of either FBXW7 or β-TrCP alone, both of which are E3 ubiquitin ligases involved in Mcl-1 degradation, only partially rescued Mcl-1 reduction induced by API-1. However, double knockdown of both E3 ubiquitin ligases ...
Targeted Kinase Degradation via the KLHDC2 Ubiquitin E3 Ligase
bioRxiv (Cold Spring Harbor Laboratory), 2022
Chemically induced protein degradation is a powerful strategy for perturbing cellular biochemistry. The predominant mechanism of action for protein degrader drugs involves induced proximity between the cellular ubiquitin conjugation machinery and the target. Unlike traditional small molecule enzyme inhibition, targeted protein degradation can clear an undesired protein from cells. We demonstrate here the use of peptide ligands for Kelch-Like Homology Domain Containing protein 2 (KLHDC2), a substrate adaptor protein and member of the cullin-2 (CUL2) ubiquitin ligase complex, for targeted protein degradation. Peptide-based bivalent compounds that can induce proximity between KLHDC2 and target proteins cause degradation of the targeted factors. The cellular activity of these compounds depends on KLHDC2 binding. This work demonstrates the utility of KLHDC2 for targeted protein degradation and exemplifies a strategy for the rational design of new peptide-based ligands useful for this purpose.