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NEDD4L is downregulated in colorectal cancer and inhibits canonical WNT signaling.

Tanksley JP, Chen X, Coffey RJ - PLoS ONE (2013)

Bottom Line: In contrast, NEDD4L mRNA, the closest homolog to NEDD4, was the most highly downregulated family member, and was significantly downregulated in all tumor stages.We also found NEDD4L protein was significantly decreased by western blotting in colorectal cancer samples compared to adjacent normal mucosa.In addition, NEDD4L, but not catalytically inactive NEDD4L, inhibited canonical WNT signaling at or below the level of β-catenin in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, United States of America.

ABSTRACT
The NEDD4 family of E3 ubiquitin ligases includes nine members. Each is a modular protein, containing an N-terminal C2 domain for cell localization, two-to-four central WW domains for substrate recognition, and a C-terminal, catalytic HECT domain, which is responsible for catalyzing the ubiquitylation reaction. Members of this family are known to affect pathways central to the pathogenesis of colorectal cancer, including the WNT, TGFβ, EGFR, and p53 pathways. Recently, NEDD4 mRNA was reported to be overexpressed in colorectal cancer, but tumor stage was not considered in the analysis. Expression of the other family members has not been studied in colorectal cancer. Herein, we determined the expression patterns of all nine NEDD4 family members in 256 patients who presented with disease ranging from premalignant adenoma to stage IV colorectal cancer. NEDD4 mRNA was significantly increased in all stages of colorectal cancer. In contrast, NEDD4L mRNA, the closest homolog to NEDD4, was the most highly downregulated family member, and was significantly downregulated in all tumor stages. We also found NEDD4L protein was significantly decreased by western blotting in colorectal cancer samples compared to adjacent normal mucosa. In addition, NEDD4L, but not catalytically inactive NEDD4L, inhibited canonical WNT signaling at or below the level of β-catenin in vitro. These findings suggest that NEDD4L may play a tumor suppressive role in colorectal cancer, possibly through inhibition of canonical WNT signaling.

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The NEDD4 family of E3 ubiquitin ligases.The nine members of the NEDD4 family are modular proteins. At their N-terminus, each has a C2 domain, which plays a role in proper cellular localization. The central portion of each protein contains two-to-four WW domains, which are responsible for target recognition. WW domains are 20–23 amino acid, Trp-based motifs that recognize PY motifs (PPXY, LPXY), as well as some phospho-Ser- or phospho-Thr-based motifs. At the C-terminus is the HECT domain, which directly conjugates an ubiquityl moiety to the target protein. The family members are grouped together by name and homology. ITCH is more closely homologous to WWP1 and 2 than to other family members.
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pone-0081514-g001: The NEDD4 family of E3 ubiquitin ligases.The nine members of the NEDD4 family are modular proteins. At their N-terminus, each has a C2 domain, which plays a role in proper cellular localization. The central portion of each protein contains two-to-four WW domains, which are responsible for target recognition. WW domains are 20–23 amino acid, Trp-based motifs that recognize PY motifs (PPXY, LPXY), as well as some phospho-Ser- or phospho-Thr-based motifs. At the C-terminus is the HECT domain, which directly conjugates an ubiquityl moiety to the target protein. The family members are grouped together by name and homology. ITCH is more closely homologous to WWP1 and 2 than to other family members.

Mentions: The nine members of the NEDD4 family of E3 ubiquitin ligases are modular proteins (Figure 1). As a whole, the NEDD4 family is known to be involved in the regulation of a number of proteins and pathways that are central to the development of CRC. Table 1 is a compilation of known substrates, signaling pathways affected, and expression levels in various cancers of all the NEDD4 family members. There is high sequence homology amongst the family members, which explains the shared targets of many of the family members. However, there are also examples of different family members having opposing effects on the same signaling pathway. For example, NEDD4 causes the downregulation of SMAD1 and CBL, which inhibits bone morphogenetic protein (BMP) signaling and activates epidermal growth factor receptor (EGFR) signaling, respectively [15], [16]. On the other hand, NEDD4L impacts transforming growth factor-β (TGFβ) signaling, but not BMP signaling, through the degradation of SMAD 2 and 3 and the type I TGFβ receptor, and abrogates EGFR signaling through the ubiquitin-mediated degradation of activated CDC42 kinase 1 (ACK1) [14], [17], [18]. Additionally, NEDD4 has been shown to downregulate the tumor suppressor PTEN [19]. However, NEDD4 was shown to promote the proliferation of CRC cells in vitro, independent of an effect on PTEN levels [10].


NEDD4L is downregulated in colorectal cancer and inhibits canonical WNT signaling.

Tanksley JP, Chen X, Coffey RJ - PLoS ONE (2013)

The NEDD4 family of E3 ubiquitin ligases.The nine members of the NEDD4 family are modular proteins. At their N-terminus, each has a C2 domain, which plays a role in proper cellular localization. The central portion of each protein contains two-to-four WW domains, which are responsible for target recognition. WW domains are 20–23 amino acid, Trp-based motifs that recognize PY motifs (PPXY, LPXY), as well as some phospho-Ser- or phospho-Thr-based motifs. At the C-terminus is the HECT domain, which directly conjugates an ubiquityl moiety to the target protein. The family members are grouped together by name and homology. ITCH is more closely homologous to WWP1 and 2 than to other family members.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3842946&req=5

pone-0081514-g001: The NEDD4 family of E3 ubiquitin ligases.The nine members of the NEDD4 family are modular proteins. At their N-terminus, each has a C2 domain, which plays a role in proper cellular localization. The central portion of each protein contains two-to-four WW domains, which are responsible for target recognition. WW domains are 20–23 amino acid, Trp-based motifs that recognize PY motifs (PPXY, LPXY), as well as some phospho-Ser- or phospho-Thr-based motifs. At the C-terminus is the HECT domain, which directly conjugates an ubiquityl moiety to the target protein. The family members are grouped together by name and homology. ITCH is more closely homologous to WWP1 and 2 than to other family members.
Mentions: The nine members of the NEDD4 family of E3 ubiquitin ligases are modular proteins (Figure 1). As a whole, the NEDD4 family is known to be involved in the regulation of a number of proteins and pathways that are central to the development of CRC. Table 1 is a compilation of known substrates, signaling pathways affected, and expression levels in various cancers of all the NEDD4 family members. There is high sequence homology amongst the family members, which explains the shared targets of many of the family members. However, there are also examples of different family members having opposing effects on the same signaling pathway. For example, NEDD4 causes the downregulation of SMAD1 and CBL, which inhibits bone morphogenetic protein (BMP) signaling and activates epidermal growth factor receptor (EGFR) signaling, respectively [15], [16]. On the other hand, NEDD4L impacts transforming growth factor-β (TGFβ) signaling, but not BMP signaling, through the degradation of SMAD 2 and 3 and the type I TGFβ receptor, and abrogates EGFR signaling through the ubiquitin-mediated degradation of activated CDC42 kinase 1 (ACK1) [14], [17], [18]. Additionally, NEDD4 has been shown to downregulate the tumor suppressor PTEN [19]. However, NEDD4 was shown to promote the proliferation of CRC cells in vitro, independent of an effect on PTEN levels [10].

Bottom Line: In contrast, NEDD4L mRNA, the closest homolog to NEDD4, was the most highly downregulated family member, and was significantly downregulated in all tumor stages.We also found NEDD4L protein was significantly decreased by western blotting in colorectal cancer samples compared to adjacent normal mucosa.In addition, NEDD4L, but not catalytically inactive NEDD4L, inhibited canonical WNT signaling at or below the level of β-catenin in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, United States of America.

ABSTRACT
The NEDD4 family of E3 ubiquitin ligases includes nine members. Each is a modular protein, containing an N-terminal C2 domain for cell localization, two-to-four central WW domains for substrate recognition, and a C-terminal, catalytic HECT domain, which is responsible for catalyzing the ubiquitylation reaction. Members of this family are known to affect pathways central to the pathogenesis of colorectal cancer, including the WNT, TGFβ, EGFR, and p53 pathways. Recently, NEDD4 mRNA was reported to be overexpressed in colorectal cancer, but tumor stage was not considered in the analysis. Expression of the other family members has not been studied in colorectal cancer. Herein, we determined the expression patterns of all nine NEDD4 family members in 256 patients who presented with disease ranging from premalignant adenoma to stage IV colorectal cancer. NEDD4 mRNA was significantly increased in all stages of colorectal cancer. In contrast, NEDD4L mRNA, the closest homolog to NEDD4, was the most highly downregulated family member, and was significantly downregulated in all tumor stages. We also found NEDD4L protein was significantly decreased by western blotting in colorectal cancer samples compared to adjacent normal mucosa. In addition, NEDD4L, but not catalytically inactive NEDD4L, inhibited canonical WNT signaling at or below the level of β-catenin in vitro. These findings suggest that NEDD4L may play a tumor suppressive role in colorectal cancer, possibly through inhibition of canonical WNT signaling.

Show MeSH
Related in: MedlinePlus