Pathobiological properties of the ubiquitin ligase <scp>N</scp>edd4<scp>L</scp> in melanoma

Kito, Yusuke; Bai, Juncheng; Goto, Naoe; Okubo, Hiroshi; Adachi, Yoshihiro; Nagayama, Tomoko; Takeuchi, Tamotsu

doi:10.1111/iep.12051

Cited by 24 publications

(24 citation statements)

References 22 publications

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“…However, there are also reports showing an increased expression of NEDD4L in prostate cancer (32). Expression of NEDD4L was also seen in a portion of melanoma samples but not detected in non-tumorous melanocytes or benign nevi tissues (33). These results indicate a potentially complex role of NEDD4L in the development of cancer.…”

Section: Discussionmentioning

confidence: 73%

“…6), decreased cell size and colony formation ability (Fig. 8), and significantly reduced the growth of melanoma cells (33), suggesting a positive role of NEDD4L in maintaining the strength of PI3K-AKT signaling. However, partial down-regulation of NEDD4L seen in many cancers may lead to an increase in PIK3CA protein level that probably promotes cell growth, suggesting a tumor suppressing role of NEDD4L through promoting PIK3CA degradation.…”

Section: Discussionmentioning

confidence: 92%

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NEDD4L Protein Catalyzes Ubiquitination of PIK3CA Protein and Regulates PI3K-AKT Signaling

Wang

Dang

Liu

et al. 2016

Journal of Biological Chemistry

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Oncogenic PIK3CA (p110␣), the catalytic subunit of class IA PI3K, plays a major role in PI3K-related cancer progression. The mechanisms underlying the dynamic regulation of PIK3CA protein levels remain unknown. Here we demonstrated that PIK3CA is regulated by polyubiquitination. We identified NEDD4L as the E3 ligase that catalyzes PIK3CA polyubiquitination, leading to its proteasome-dependent degradation. NEDD4L ubiquitinates both the free and regulatory subunitbound PIK3CA but does not ubiquitinate the regulatory subunit of PI3K. Overexpression of NEDD4L accelerates the turnover rate of PIK3CA, whereas suppression of NEDD4L results in not only the accumulation of PIK3CA but also a paradoxical decrease of AKT activation. Thus, we propose that NEDD4L negatively regulates PIK3CA protein levels via ubiquitination and is required for the maintenance of PI3K-AKT signaling pathway.Class IA phosphoinositide 3-kinases (PI3Ks) are lipid kinases that integrate signals from growth factors and hormones to regulate multiple cellular process including growth, proliferation, migration, and survival (1). In response to activation of various growth factor receptors, PI3K is recruited to the cell membrane to catalyze the production of phosphoinositide-3,4,5-trisphosphate, a second messenger required for the activation of a series of downstream kinases (1, 2). Class IA PI3K is composed of a catalytic subunit (p110) and a regulatory subunit (p85), which are demonstrated to form an obligatory heterodimer (3). PIK3CA (p110␣), a major isoform of the catalytic subunits, is widely expressed in various tissues (4). Somatic mutations in PIK3CA occur frequently in cancers of the breast, colon, endometrium, and prostate as well as glioblastomas (5-7). Gain of PIK3CA copy number leads to increased PIK3CA protein levels and is also associated with human cancers (4,8,9). These observations indicate that dysregulation of PI3K plays an important role in cancer emergence and development, underscoring the significance of understanding the regulation mechanisms of PI3K signaling pathway.PI3K function can be modulated via its gene expression or its association with Ras, receptor-tyrosine kinases and other adaptor proteins such as insulin receptor substrate1/2 (IRS1/2). It can also be regulated through post-translational modifications. For instance, previous reports demonstrate that the p85 regulatory subunit can be polyubiquitinated and negatively regulated by the E3 ubiquitin ligase Cbl-b in T cells without affecting its protein level (10, 11). In addition, recent work shows that dephosphorylation of the p110-free p85␤ regulatory subunit leads to its degradation through F-box protein FBXL2 (12). Importantly, the catalytic subunit PIK3CA may also be subject to a similar regulation: that is, a dynamic cycle of proteasomedependent degradation and resynthesis of PIK3CA was observed in response to the stimulation of epidermal growth factor (13).To further understand the regulation of PIK3CA, we developed an in vitro ubiquitination assay for PIK3CA. Usin...

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 92%

NEDD4L Protein Catalyzes Ubiquitination of PIK3CA Protein and Regulates PI3K-AKT Signaling

Wang

Dang

Liu

et al. 2016

Journal of Biological Chemistry

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“…Increased NEDD4L level was also reported in many cases of cutaneous invasive and nodal metastatic melanoma, but not in non-tumorous melanocytes or benign tissue specimens [68]. Immunohistochemical staining revealed that NEDD4L was present in 34 out of 79 cutaneous melanomas and in 9 of 32 nodal metastatic melanomas, while undetected in any non-tumorous melanocytes or in benign nevi tissues.…”

Section: Nedd4l (Nedd4-2)mentioning

confidence: 79%

“…Immunohistochemical staining revealed that NEDD4L was present in 34 out of 79 cutaneous melanomas and in 9 of 32 nodal metastatic melanomas, while undetected in any non-tumorous melanocytes or in benign nevi tissues. Consequently, silencing of NEDD4L expression significantly reduced the melanoma cells growth; whereas NEDD4L overexpression accelerated it both in culture and in mice [68].…”

Section: Nedd4l (Nedd4-2)mentioning

confidence: 95%

Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

Zou

Levy-Cohen

Blank

2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

106

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“…As an E3 ubiquitin ligase of the Nedd4 family, Nedd4-2 probably modulates and binds to multiple membrane proteins to aid in their internalization and turnover (5,6). Dysfunctions of Nedd4-2 have been implicated in many human pathologies through the targeted membrane proteins; for example, inhibition of the interaction between Nedd4-2 and epithelial sodium channel (ENaC) leads to Liddle's syndrome (7), downregulation of voltage-gated sodium channels by Nedd4-2 contributes to neuropathic pain (8), altered levels of Nedd4-2 are linked to multiple tumor types (9,10) and genetic variation in Nedd4-2 is associated with hypertension (11). Therefore, the present study examined post-translational modifications to explore the potential mechanism of 20-HETE-regulated Nedd4-2 expression in the CYP4F2 transgenic mouse model.…”

Section: Introductionmentioning

confidence: 99%

20-Hydroxyeicosatetraenoic acid regulates the expression of Nedd4-2 in kidney and liver through a neddylation modification pathway

Zhao

Zhang

Lai

et al. 2017

Molecular Medicine Reports

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The present study aimed to test whether 20-hydroxyeicosatetraenoic acid (20‑HETE) affected neddylation modification of E3‑ligase Nedd4‑2 (neural precursor cell expressed, developmentally down‑regulated 4‑like, E3 ubiquitin protein ligase). A cytochrome P450 family 4 subfamily F member 2 (CYP4F2) transgenic mouse model that overproduces 20‑HETE in the kidney and the liver was used in the present study. Transgenic mice with high salt intake exhibited increased activation of Nedd4‑2‑mediated ubiquitin‑proteasome pathway. Nedd4‑2 expression is increased in the kidney and decreased in the liver of transgenic mice compared with wild‑type mice. Subsequently, co‑immunoprecipitation analysis indicated that Nedd4‑2 was modified by Nedd8, and the level of neddylation on Nedd4‑2 was reduced in the kidney and increased in the liver of transgenic mice compared with controls. In addition, sentrin‑specific protease 8 (Senp8), a deneddylation enzyme, is expressed higher in the kidney and lower in the liver of transgenic mice compared with wild‑type controls. The function of 20‑HETE on modulation of Nedd4‑2 were also confirmed in mouse M1 kidney and mouse NCTC1469 liver cell lines, and the function was restored by neddylation inhibitor MLN4924 Data from the present study demonstrated that 20‑HETE upregulated the expression of Nedd4‑2 in the kidney and downregulated expression in the liver through the neddylation modification pathway, at least partly, depending on the effects on Senp8 deneddylation.

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Pathobiological properties of the ubiquitin ligase Nedd4L in melanoma

Cited by 24 publications

References 22 publications

NEDD4L Protein Catalyzes Ubiquitination of PIK3CA Protein and Regulates PI3K-AKT Signaling

NEDD4L Protein Catalyzes Ubiquitination of PIK3CA Protein and Regulates PI3K-AKT Signaling

Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

20-Hydroxyeicosatetraenoic acid regulates the expression of Nedd4-2 in kidney and liver through a neddylation modification pathway

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