Disease relevance of WWP1

• We also show that WWP1, WWP2, or Itch ubiquitin ligase recruitment promotes PPXY-dependent virion release, and that this function requires that the HECT ubiquitin ligase domain be catalytically active [1].
• A dominant-negative (DN) mutant of WWP1 could inhibit budding of the intact HTLV-1 virus [2].
• WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer [3].
• In PC-3 prostate cancer cells, WWP1 knockdown significantly suppressed cell proliferation and enhanced TGFbeta-mediated growth inhibition [4].

High impact information on WWP1

• Here, we show that PPXY-dependent viral budding is unusually sensitive to inhibitory fragments derived from specific HECT ubiquitin ligases, namely WWP1 and WWP2 [1].
• We found that WWP1 formed a protein complex with KLF5 in vivo and in vitro [5].
• A PY motif in a transactivation domain of KLF5 is necessary for its interaction with WWP1 [5].
• Furthermore, WWP1 mediated the ubiquitination and degradation of KLF5, and the catalytic cysteine residue of WWP1 is essential for its function [5].
• Human Kruppel-like factor 5 is a target of the E3 ubiquitin ligase WWP1 for proteolysis in epithelial cells [5].

Biological context of WWP1

• A Caenorhabditis elegans gene was cloned encoding a HECT domain protein (CeWWP1), which was highly homologous to murine and human WWP1 [6].
• A HECT domain ubiquitin ligase closely related to the mammalian protein WWP1 is essential for Caenorhabditis elegans embryogenesis [6].
• We show that alternative splicing affects the domain structure of WWP1, with forms that contain or lack an N-terminal C2 domain [7].
• One splice form generates, through the introduction of a reading frame shift, a C2 domain-only form of WWP1 [7].
• Here, we provide the first evidence that PKA-mediated phosphorylation of Ser(66)regulates the interaction of ezrin with WWOX, a WW domain-containing protein [8].

Anatomical context of WWP1

• Finally, WWP1 was amplified and overexpressed in some cancer cell lines from the prostate and breast, which negatively regulated the function of KLF5 in gene regulation [5].
• Coexpression of human Notch1 (hN1) depleted WWP1 from the nucleus to colocalise with hN1 in early endosomes, dependent on the presence of the C-terminal HECT domain [9].
• As expected, WWP1 was expressed, like ENaC, in the bronchiolar epithelium [10].

Physical interactions of WWP1

• Furthermore we found that full-length expressed WWP1 could interact in vitro with the cytoplasmic domain of human Notch1 [9].
• Here, we demonstrate that WWP1 interacts with KLF2 in vivo and mediates both poly-ubiquitination and proteasomal degradation of KLF2 [11].

Enzymatic interactions of WWP1

• However, unlike Smurfs, WWP1 failed to ubiquitinate R-Smads and SnoN [12].

Regulatory relationships of WWP1

• Using a TGF-beta-responsive reporter in mammalian cells, we found that WWP1 inhibited transcriptional activities induced by TGF-beta [12].
• Our experiments demonstrate for the first time that WWP1 promotes ubiquitination and degradation of KLF2 and is not involved in the ubiquitin-transfer reaction [11].

Other interactions of WWP1

• This screen yielded three ubiquitin-protein ligases, WWP1, WWP2, and AIP4, all of which belong to the HECT family and contain multiple WW domains [13].
• In mammalian cells, WWP1 functions as a cofactor by binding LKLF and suppressing transactivation [14].
• Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1) [12].
• Here we report the cloning and characterization of a novel human WW domain-containing protein, PCIF1 (phosphorylated CTD interacting factor 1) [15].
• Characterization of KIBRA, a novel WW domain-containing protein [16].

Analytical, diagnostic and therapeutic context of WWP1

• Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase [17].
• To establish whether WWP1 is co-expressed with ENaC, we employed in situ hybridisation, immunohistochemistry and Western blotting to determine the expression of WWP1 in various tissues and cell lines, including those known to express ENaC [10].

References