Emerging role of Lys-63 ubiquitination in protein kinase and phosphatase activation and cancer development

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Oncogene (Impact Factor: 8.46). 08/2010; 29(32):4493-503. DOI: 10.1038/onc.2010.190
Source: PubMed

ABSTRACT Ubiquitination is an important post-translational modification that has a pivotal role in numerous biological functions, such as cell growth, proliferation, apoptosis, DNA damage response, innate immune response and neuron degeneration. Although ubiquitination is thought to achieve these functions by targeting proteins for proteasome-dependent degradation, recent studies suggest that ubiquitination also has nonproteolytic functions, such as protein trafficking, kinase and phosphatase activation, which are involved in cell survival and cancer development. These progresses have advanced our current understanding of the novel functions of ubiquitination in signal transduction pathways and may provide novel paradigms for the treatment of human cancers.

Download full-text


Available from: Wei-Lei Yang, Nov 12, 2014
12 Reads
  • Source
    • "Ubiquitin is a ubiquitous and conserved protein composed of 76 amino acid. Ubiquitin-proteasome pathway begins with the attachment of ubiquitin to selected protein [12]. The sequential biochemical reactions involve three ubiquitin-related enzymes: ubiquitin activating enzyme (E1 enzyme), ubiquitin conjugating enzyme (E2 enzyme) and ubiquitin ligase (E3 ligase). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Increasing evidence suggest that ubiquitin-proteasome system (UPS) plays a key role in tumorigenesis. HERC4 is a recently identified ubiqutin ligase. However, the expression status and biological functions of HERC4 in cancers are not clearly. We evaluated the HERC4 expression in breast cancer cell lines and breast tumor tissues by quantitative real-time PCR and western blot analysis. To investigate the clinicopathological significance of HERC4, immunohistochemistry analysis for HERC4 was performed on a tissue microarray including 13 benign fibroadenoma, 15 intraductal carcinoma, 120 histologically confirmed invasive ductal carcinoma. Receiver operating characteristic (ROC) analysis was applied to determine the optimal cut-off score for positive expression of HERC4, when HERC4 positive expression percentage was above 60%, tumor was defined as "positive". HERC4 was up-regulated in breast cancer cell lines and breast tumor tissues compared to non-tumorigenic cell line and adjacent normal breast tissues. According to ROC analysis, HERC4 positive expression was detected in 1/16 (6.3%) of normal breast tissue, in 3/13 (23.1%) of fibroadenoma, in 6/15(40%) of intraductal carcinoma and 66/120 (55%) of invasive ductal carcinoma. Positive expression of HERC4 was positively correlated with pT status, pN status, clinical stage and histological grade of patients with invasive ductal carcinoma (p < 0.05). Our findings suggest that HERC4 was a significant diagnostic marker for invasive ductal carcinoma of the breast.
    Cancer Cell International 11/2013; 13(1):113. DOI:10.1186/1475-2867-13-113 · 2.77 Impact Factor
  • Source
    • "Ubiquitin proteasome pathway and tumorigenesis 727 Int J Clin Exp Pathol 2012;5(8):726-738 uitously expressed in the organisms of eukaryotic kingdom [5] [6]. The ubiquitin proteasome pathway first processes the attachment of ubiquitin to a target protein which involves three critical enzymes, the ubiquitin activating enzyme or E1 enzyme, the ubiquitin conjugating enzyme or E2 enzyme, and the ubiquitin ligase or E3 ligase [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Accumulated evidence supports that the ubiquitin proteasome pathway (UPP) plays a crucial role in protein metabolism implicated in the regulation of many biological processes such as cell cycle control, DNA damage response, apoptosis, and so on. Therefore, alterations for the ubiquitin proteasome signaling or functional impairments for the ubiquitin proteasome components are involved in the etiology of many diseases, particularly in cancer development. In this minireview, we first give a brief outline for the ubiquitin proteasome pathway, we then discuss with focus for the ubiquitin proteasome pathway in the regulation of cell cycle control and DNA damage response, the relevance for the altered regulation of these signaling pathways in tumorigenesis is also reviewed. We finally assess and summarize the advancement for targeting the ubiquitin proteasome pathway in cancer therapy. A better understanding of the biological functions underlying ubiquitin regulatory mechanisms would provide us a wider prospective on cancer treatment.
    International journal of clinical and experimental pathology 10/2012; 5(8):726-38. · 1.89 Impact Factor
  • Source
    • "Recently, more and more nonproteolytic functions of ubiquitination have been discovered. It can regulate the transcription activity of transcription factors (Herrera and Triezenberg, 2004), and modulate the enzyme activity and protein subcellular localization (Chen and Sun, 2009; Komander, 2009; Yang et al., 2010). We propose that SIE3 may exert its positive effect on symbiotic signaling via ubiquitination of SymRK. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The symbiosis receptor kinase (SymRK) is required for morphological changes of legume root hairs triggered by rhizobial infection. How protein turnover of SymRK is regulated and how the nodulation factor signals are transduced downstream of SymRK are not known. In this report, a SymRK-interacting E3 ubiquitin ligase (SIE3) was shown to bind and ubiquitinate SymRK. The SIE3-SymRK interaction and the ubiquitination of SymRK were shown to occur in vitro and in planta. SIE3 represents a new class of plant-specific E3 ligases that contain a unique pattern of the conserved CTLH (for C-terminal to LisH), CRA (for CT11-RanBPM), and RING (for Really Interesting New Gene) domains. Expression of SIE3 was detected in all tested tissues of Lotus japonicus plants, and its transcript level in roots was enhanced by rhizobial infection. The SIE3 protein was localized to multiple subcellular locations including the nuclei and plasma membrane, where the SIE3-SymRK interaction took place. Overexpression of SIE3 promoted nodulation in transgenic hairy roots, whereas downregulation of SIE3 transcripts by RNA interference inhibited infection thread development and nodule organogenesis. These results suggest that SIE3 represents a new class of E3 ubiquitin ligase, acts as a regulator of SymRK, and is involved in rhizobial infection and nodulation in L. japonicus.
    Plant physiology 07/2012; 160(1):106-17. DOI:10.1104/pp.112.199000 · 6.84 Impact Factor
Show more