YAP1 Recruits c-Abl to Protect Angiomotin-Like 1 from Nedd4-Mediated Degradation

Abstract

BackgroundTissue development and organ growth require constant remodeling of cell-cell contacts formed between epithelial cells. The Hippo signaling cascade curtails organ growth by excluding the transcriptional co-activator Yes Associated Protein 1 (YAP1) from the nucleus. Angiomotin family members recruit YAP1 to tight junctions [1], but whether YAP1 plays a specific role outside of the nucleus is currently unknown.Methodology/Principal FindingsThe present study demonstrates that the E3 ubiquitin ligase Nedd4.2 targets Angiomotin-like 1 (AMOTL1), a family member that promotes the formation of epithelial tight junctions, for ubiquitin-dependent degradation. Unexpectedly, YAP1 antagonizes the function of Nedd4.2, and protects AMOTL1 against Nedd4.2-mediated degradation. YAP1 recruits c-Abl, a tyrosine kinase that binds and phosphorylates Nedd4.2 on tyrosine residues, thereby modifying its ubiquitin-ligase activity.Conclusions/SignificanceOur results uncover a novel function for cytoplasmic YAP1. YAP1 recruits c-Abl to protect AMOTL1 against Nedd4.2-mediated degradation. Thus, YAP1, excluded from the nucleus, contributes to the maintenance of tight junctions.

Amot130 Adapts Atrophin-1 Interacting Protein 4 to Inhibit Yes-associated Protein Signaling and Cell Growth

“…A similar prece- dence is seen with Nedd4 ligases (43,44) as well as YAP2 (45). However, this study indicates that YAP2 achieves this by binding the P-Y1 and P-Y2 motifs of Amot130 and not through the P-Y3 motif (9,30). Consistently, YAP2 strongly binds AmotL2 (9), which lacks a P-Y3 motif.…”

“…GST-tagged YAP2-WW1, -WW2, and -WW1 and -2 domains bound the P-Y2 peptide with K d values of 6.6, 4.4, and 2.9 M respectively ( Table 1). P-Y3 was not examined as it does not bind YAP2 (30). Consistent with YAP2 requiring both P-Y1 and P-Y2 for binding full-length protein, it showed almost no detectable association with Amot130 P-Y1F or P-Y2F mutants (Fig.…”

Angiomotin prevents pluripotent lineage differentiation in mouse embryos via Hippo pathway-dependent and -independent mechanisms

“…A third motif conserved across all motins, LPTY, has been suggested to mediate interaction between Yap and Amotl1 (ref. 26). These motifs therefore represent a Yap-dependent but Hippo pathway-independent activity of Amot.…”

“…Moreover, one of the E3 ubiquitin ligases able to promote Amot degradation27, NEDD4L, is expressed two-fold higher in TE than in ICM progenitors (Krzysztof Wicher, Sarah Graham and Magdalena Zernicka-Goetz, unpublished observations), thus giving the potential of reducing Amot levels in TE. In addition, cytoplasmic Yap has been found to protect Amotl1 from NEDD4-mediated degradation26, raising an interesting possibility that Yap could act in a positive feedback loop to prevent Amot degradation in the ICM.…”

Tyrosine phosphorylation of WW proteins

“…The example of ErbB-4 association with Yap represents an example of phosphorylation of the PPxY motif affecting association with the WW domain protein. 40 Nedd4.1 is also regulated by tyrosine phosphorylation. FGFR1 is ubiquitinated by Nedd4.1 following FGFR activation, which leads to receptor internalization and degradation.…”