The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation. Nat Med

Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
Nature medicine (Impact Factor: 28.05). 01/2008; 13(12):1504-9. DOI: 10.1038/nm1686
Source: PubMed

ABSTRACT Metastasis is the primary cause of mortality from cancer, but the mechanisms leading to metastasis are poorly understood. In particular, relatively little is known about metastasis in cancers of mesenchymal origins, which are known as sarcomas. Approximately ten proteins have been characterized as 'metastasis suppressors', but how these proteins function and are regulated is, in general, not well understood. Gp78 (also known as AMFR or RNF45) is a RING finger E3 ubiquitin ligase that is integral to the endoplasmic reticulum (ER) and involved in ER-associated degradation (ERAD) of diverse substrates. Here we report that expression of gp78 has a causal role in the metastasis of an aggressive human sarcoma and that this prometastatic activity requires the E3 activity of gp78. Further, gp78 associates with and targets the transmembrane metastasis suppressor, KAI1 (also known as CD82), for degradation. Suppression of gp78 increases KAI1 abundance and reduces the metastatic potential of tumor cells, an effect that is largely blocked by concomitant suppression of KAI1. An inverse relationship between these proteins was confirmed in a human sarcoma tissue microarray. Whereas most previous efforts have focused on genetic mechanisms for the loss of metastasis suppressor genes, our results provide new evidence for post-translational downregulation of a metastasis suppressor by its ubiquitin ligase, resulting in abrogation of its metastasis-suppressing effects.

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    • "Interestingly, substantially more ubiquitin conjugated MRP2 was detected in cells cotransfected with GFP-Ub K0 than with GFP-Ub WT , supporting that polyubiquitination of MRP2 leads to its degradation [25]. As ubiquitin conjugation is the rate limiting step in target protein degradation [26] [27], we examined which ubiquitin ligase E3s was responsible for MRP2 ubiquitination in human cholestatic livers, i.e., GP78, TEB4 and HRD1. As shown in Figure 6C and D, only GP78 expression was significantly increased at both mRNA and protein levels (2.1-flod, p<0.05 and 4.2-fold, p<0.01 of control livers, respectively), whereas hepatic expression of TEB4 and HRD1 did not change. "
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    Journal of Hepatology 07/2015; DOI:10.1016/j.jhep.2015.07.016 · 10.40 Impact Factor
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    • "As shown in Figure 3F, Amfr À/À MEFs showed an increased number of HSV-1-GFP-positive cells. AMFR Catalyzes K27-Linked Polyubiquitination of STING As an E3 ubiquitin ligase in ERAD (ER-associated protein degradation ), AMFR catalyzes the polyubiquitination of HMG-CoA reductase (HMGCR) and the metastasis suppressor KAI1, and promotes their proteasome-dependent degradation (Song et al., 2005; Tsai et al., 2007). Our in vitro ubiquitination assays confirmed that AMFR could catalyze the formation of polyubiquitin chains, whereas AMFR C2S could not (Figure 4B). "
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    Immunity 12/2014; 41(6):919-933. DOI:10.1016/j.immuni.2014.11.011 · 19.75 Impact Factor
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    • "Glycoprotein 78 (gp78) is a cell surface receptor that also functions as an E3 ubiquitin ligase in the endoplasmic reticulum-associated degradation pathway. A study by Tsai et al (15) reported that the expression of gp78 exhibits a causal role in the metastasis of an aggressive human sarcoma. Furthermore, gp78 is associated with, and targets, the transmembrane metastasis suppressor, KIA1, for degradation. "
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