Cargando…
AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation
Contact inhibition is a key cellular phenomenon that prevents cells from hyper-proliferating upon reaching confluence. Although not fully characterized, a critical driver of this process is the Hippo signaling pathway, whose downstream effector yes-associated protein plays pivotal roles in cell grow...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Life Science Alliance LLC
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372784/ https://www.ncbi.nlm.nih.gov/pubmed/34404733 http://dx.doi.org/10.26508/lsa.202000953 |
_version_ | 1783739835274493952 |
---|---|
author | Hwang, Daehee Kim, Miju Kim, Soyeon Kwon, Mi Ra Kang, Ye-Seul Kim, Dahyun Kang, Ho-Chul Lim, Dae-Sik |
author_facet | Hwang, Daehee Kim, Miju Kim, Soyeon Kwon, Mi Ra Kang, Ye-Seul Kim, Dahyun Kang, Ho-Chul Lim, Dae-Sik |
author_sort | Hwang, Daehee |
collection | PubMed |
description | Contact inhibition is a key cellular phenomenon that prevents cells from hyper-proliferating upon reaching confluence. Although not fully characterized, a critical driver of this process is the Hippo signaling pathway, whose downstream effector yes-associated protein plays pivotal roles in cell growth and differentiation. Here, we provide evidence that the E3 ligase WWP1 (WW-domain containing protein 1) mono-ubiquitinates AMOTL2 (angiomotin-like 2) at K347 and K408. Mono-ubiquitinated AMOTL2, in turn, interacts with the kinase LATS2, which facilitates recruitment of the upstream Hippo pathway component SAV1 and ultimately promotes yes-associated protein phosphorylation and subsequent cytoplasmic sequestration and/or degradation. Furthermore, contact inhibition induced by high cell density promoted the localization and stabilization of WWP1 at cell junctions, where it interacted with Crumbs polarity proteins. Notably, the Crumbs complex was functionally important for AMOTL2 mono-ubiquitination and LATS activation under high cell density conditions. These findings delineate a functionally important molecular mechanism in which AMOTL2 mono-ubiquitination by WWP1 at cell junctions and LATS activation are tightly coupled to upstream cell density cues. |
format | Online Article Text |
id | pubmed-8372784 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Life Science Alliance LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-83727842021-08-26 AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation Hwang, Daehee Kim, Miju Kim, Soyeon Kwon, Mi Ra Kang, Ye-Seul Kim, Dahyun Kang, Ho-Chul Lim, Dae-Sik Life Sci Alliance Research Articles Contact inhibition is a key cellular phenomenon that prevents cells from hyper-proliferating upon reaching confluence. Although not fully characterized, a critical driver of this process is the Hippo signaling pathway, whose downstream effector yes-associated protein plays pivotal roles in cell growth and differentiation. Here, we provide evidence that the E3 ligase WWP1 (WW-domain containing protein 1) mono-ubiquitinates AMOTL2 (angiomotin-like 2) at K347 and K408. Mono-ubiquitinated AMOTL2, in turn, interacts with the kinase LATS2, which facilitates recruitment of the upstream Hippo pathway component SAV1 and ultimately promotes yes-associated protein phosphorylation and subsequent cytoplasmic sequestration and/or degradation. Furthermore, contact inhibition induced by high cell density promoted the localization and stabilization of WWP1 at cell junctions, where it interacted with Crumbs polarity proteins. Notably, the Crumbs complex was functionally important for AMOTL2 mono-ubiquitination and LATS activation under high cell density conditions. These findings delineate a functionally important molecular mechanism in which AMOTL2 mono-ubiquitination by WWP1 at cell junctions and LATS activation are tightly coupled to upstream cell density cues. Life Science Alliance LLC 2021-08-17 /pmc/articles/PMC8372784/ /pubmed/34404733 http://dx.doi.org/10.26508/lsa.202000953 Text en © 2021 Hwang et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Articles Hwang, Daehee Kim, Miju Kim, Soyeon Kwon, Mi Ra Kang, Ye-Seul Kim, Dahyun Kang, Ho-Chul Lim, Dae-Sik AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation |
title | AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation |
title_full | AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation |
title_fullStr | AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation |
title_full_unstemmed | AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation |
title_short | AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation |
title_sort | amotl2 mono-ubiquitination by wwp1 promotes contact inhibition by facilitating lats activation |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372784/ https://www.ncbi.nlm.nih.gov/pubmed/34404733 http://dx.doi.org/10.26508/lsa.202000953 |
work_keys_str_mv | AT hwangdaehee amotl2monoubiquitinationbywwp1promotescontactinhibitionbyfacilitatinglatsactivation AT kimmiju amotl2monoubiquitinationbywwp1promotescontactinhibitionbyfacilitatinglatsactivation AT kimsoyeon amotl2monoubiquitinationbywwp1promotescontactinhibitionbyfacilitatinglatsactivation AT kwonmira amotl2monoubiquitinationbywwp1promotescontactinhibitionbyfacilitatinglatsactivation AT kangyeseul amotl2monoubiquitinationbywwp1promotescontactinhibitionbyfacilitatinglatsactivation AT kimdahyun amotl2monoubiquitinationbywwp1promotescontactinhibitionbyfacilitatinglatsactivation AT kanghochul amotl2monoubiquitinationbywwp1promotescontactinhibitionbyfacilitatinglatsactivation AT limdaesik amotl2monoubiquitinationbywwp1promotescontactinhibitionbyfacilitatinglatsactivation |