β-Arrestin and Mdm2 Mediate IGF-1 Receptor-stimulated ERK Activation and Cell Cycle Progression

Girnita, Leonard; Shenoy, Sudha K.; Sehat, Bita; Vasilcanu, Radu; Vasilcanu, Daiana; Girnita, Ada; Lefkowitz, Robert J.; Larsson, Olle

doi:10.1074/jbc.m611526200

Cited by 119 publications

(147 citation statements)

References 40 publications

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“…Adenovirus of endoglin and GFP were generated according to the manufacturer's instructions (Stratagene). The siRNA sequence targeting mouse ␤-arrestin2 5Ј-AAGGACCGGA-AAGUGUUCGUG-3 is reported elsewhere (43). Briefly, knockdown of ␤-arrestin2 expression was achieved by nucleofection of 15 g of RNA in 10 6 cells and incubated for 72 h.…”

Section: Methodsmentioning

confidence: 99%

The Interaction of Endoglin with β-Arrestin2 Regulates Transforming Growth Factor-β-mediated ERK Activation and Migration in Endothelial Cells

Lee

Blobe

2007

Journal of Biological Chemistry

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In endothelial cells, transforming growth factor ␤ (TGF-␤) signals through two distinct pathways to regulate endothelial cell proliferation and migration, the ALK-1/Smads 1/5/8 pathway and the ALK-5/Smads 2/3 pathway. TGF-␤ signaling through these pathways is further regulated in endothelial cells by the endothelial specific TGF-␤ superfamily co-receptor, endoglin. The importance of endoglin, ALK-1, and ALK-5 in endothelial biology is underscored by the embryonic lethal phenotypes of knock-outs in mice due to defects in angiogenesis, and by the presence of disease-causing mutations in these genes in human vascular diseases. However, the mechanism of action of endoglin is not well defined. Here we define a novel interaction between endoglin and the scaffolding protein ␤-arrestin2. Both co-immunoprecipitation and fluorescence confocal studies demonstrate the specific interaction between endoglin and ␤-arrestin2 in endothelial cells, enhanced by ALK-1 and to a lesser extent by the type II TGF-␤ receptor. The endoglin/␤-arrestin2 interaction results in endoglin internalization and co-accumulation of endoglin and ␤-arrestin2 in endocytic vesicles. Whereas endoglin did not have a direct impact on either Smad 2/3 or Smad 1/5/8 activation, endoglin antagonized TGF-␤-mediated ERK signaling, altered the subcellular distribution of activated ERK, and inhibited endothelial cell migration in a manner dependent on the ability of endoglin to interact with ␤-arrestin2. Reciprocally, small interfering RNA-mediated silencing of endogenous ␤-arrestin2 expression restored TGF-␤-mediated ERK activation and increased endothelial cell migration in an endoglin-dependent manner. These studies define a novel function for endoglin, and further expand the roles mediated by the ubiquitous scaffolding protein ␤-arrestin2.

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Section: Methodsmentioning

confidence: 99%

The Interaction of Endoglin with β-Arrestin2 Regulates Transforming Growth Factor-β-mediated ERK Activation and Migration in Endothelial Cells

Lee

Blobe

2007

Journal of Biological Chemistry

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“…, or 10 min (C). They were harvested and analyzed for ZNF143 expression using immunoblotting (A, C) and for ROS generation using flow cytometry, as described in Figure 2C 1998; Girnita et al, 2007). IGF-1 also increases reactive oxygen species (ROS) generation in treated cells and contributes to the proliferation with the help of GAIP interacting protein, Cterminus (GIPC) (Choi et al, 2010) and migration of vascular smooth muscle cells via Nox4 and Rac1 (Meng et al, 2008;Vardatsikos et al, 2009).…”

Section: Phosphatidylinositol-3-kinase (Pi3-kinase) and Nadph Oxidasementioning

confidence: 99%

IGF-1 induces expression of zinc-finger protein 143 in colon cancer cells through phosphatidylinositide 3-kinase and reactive oxygen species

Paek

Kim

et al. 2010

Exp Mol Med

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Expression of zinc-finger protein 143 (ZNF143), a human homolog of the Xenopus transcriptional activator protein Staf, is induced by various DNA-damaging agents including etoposide, doxorubicin, and γ-irradiation. ZNF143 binds to cisplatin-modified DNA, and its levels are increased in cancer cells that are resistant to anticancer drugs, including cisplatin, suggesting that it plays a role in carcinogenesis and cancer cell survival. However, the mechanism of ZNF143 induction in cancer cells remains unclear. Both insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) have been reported to be overexpressed in cancer cells and to be related to anticancer drug resistance, but the identity of the relevant signaling mediators is still being investigated. In the present study, we observed that IGF-1 was able to induce ZNF143 expression in HCT116 human colon cancer cells and that wortmannin, an inhibitor of phosphatidylinositide 3-kinase (PI3-kinase), inhibited this induction, as did diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, and monodansylcardavarine (MDC), a receptor internalization inhibitor. Treatment with MDC decreased the IGF-1-stimulated generation of reactive oxygen species. Taken together, these data suggest that IGF-1 induces ZNF143 expression in cancer cells via PI3-kinase and reactive oxygen species generation during receptor internalization.

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“…Phosphorylation of the receptor has for a long time been considered to be the most important activating signal; however, recent data have shed light on ubiquitination of IGF-IR and its role in mediating biological functions (4,(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Identification of c-Cbl as a New Ligase for Insulin-like Growth Factor-I Receptor with Distinct Roles from Mdm2 in Receptor Ubiquitination and Endocytosis

et al. 2008

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The insulin-like growth factor receptor (IGF-IR) plays several pivotal roles in cancer. Although most studies on the function of the IGF-IR have been attributed to kinase-dependent signaling, recent findings by our group and others have implicated biological roles mediated by ubiquitination of the receptor. As previously reported, the E3 ligases Mdm2 and Nedd4 mediate IGF-IR ubiquitination. Here we show that c-Cbl is a novel E3 ligase for IGF-IR. On ligand stimulation, both Mdm2 and c-Cbl associate with IGF-IR and mediate receptor polyubiquitination. Whereas Mdm2 catalyzed lysine 63 (K63) chain ubiquitination, c-Cbl modified IGF-IR through K48 chains. Mdm2-mediated ubiquitination occurred when cells were stimulated with a low concentration (5 ng/mL) of IGF-I, whereas c-Cbl required high concentrations (50-100 ng/mL). Mdm2-ubiquitinated IGF-IR was internalized through the clathrin endocytic pathway whereas c-Cbl-ubiquitinated receptors were endocytosed via the caveolin route. Taken together, our results show that c-Cbl constitutes a new ligase responsible for the ubiquitination of IGF-IR and that it complements the action of Mdm2 on ubiquitin lysine residue specificity, responsiveness to IGF-I, and type of endocytic pathway used. The actions and interactions of Mdm2 and c-Cbl in the ubiquitination and endocytosis of IGF-IR may have implications in cancer. In addition, identification and functional characterization of new E3 ligases are important in itself because therapeutic targeting of substrate-specific E3 ligases is likely to represent a critical strategy in future cancer treatment.

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β-Arrestin and Mdm2 Mediate IGF-1 Receptor-stimulated ERK Activation and Cell Cycle Progression

Cited by 119 publications

References 40 publications

The Interaction of Endoglin with β-Arrestin2 Regulates Transforming Growth Factor-β-mediated ERK Activation and Migration in Endothelial Cells

The Interaction of Endoglin with β-Arrestin2 Regulates Transforming Growth Factor-β-mediated ERK Activation and Migration in Endothelial Cells

IGF-1 induces expression of zinc-finger protein 143 in colon cancer cells through phosphatidylinositide 3-kinase and reactive oxygen species

Identification of c-Cbl as a New Ligase for Insulin-like Growth Factor-I Receptor with Distinct Roles from Mdm2 in Receptor Ubiquitination and Endocytosis

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