RT Journal Article SR Electronic T1 AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202000953 DO 10.26508/lsa.202000953 VO 4 IS 10 A1 Daehee Hwang A1 Miju Kim A1 Soyeon Kim A1 Mi Ra Kwon A1 Ye-Seul Kang A1 Dahyun Kim A1 Ho-Chul Kang A1 Dae-Sik Lim YR 2021 UL https://www.life-science-alliance.org/content/4/10/e202000953.abstract AB 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.