Role of α-Catenin and its mechanosensing properties in the regulation of Hippo/YAP-dependent tissue growth

Abstract

α-catenin is a key protein of adherens junctions (AJs) with mechanosensory properties. It also acts as a tumor suppressor that limits tissue growth. Here we analyzed the function of Drosophila α-Catenin (α-Cat) in growth regulation of the wing epithelium. We found that different α-Cat levels led to a differential activation of Hippo/Yorkie or JNK signaling causing tissue overgrowth or degeneration, respectively. α-Cat can modulate Yorkie-dependent tissue growth through recruitment of Ajuba, a negative regulator of Hippo signaling, to AJs but also through a mechanism that does not involve junctional recruitment of Ajuba. Further, both mechanosensory regions of α-Cat, the M region and the actin-binding domain (ABD), contribute to growth regulation. Whereas M is dispensable for α-Cat function in the wing, individual M domains (M1, M2, M3) have opposing effects on growth regulation. In particular, M1 limits Ajuba recruitment. Loss of M1 cause Ajuba hyper-recruitment to AJs promoting tissue-tension independent overgrowth. Although M1 binds Vinculin, Vinculin it is not responsible for this effect. Moreover, disruption of mechanosensing of the α-Cat actin-binding domain affects tissue growth, with enhanced actin interactions stabilizing junctions and leading to tissue overgrowth. Together, our findings indicate that α-Cat acts through multiple mechanisms to control tissue growth, including regulation of AJ stability, mechanosensitive Ajuba recruitment, and dynamic direct F-actin interactions.

Vinculin recruitment to α-catenin halts the differentiation and maturation of enterocyte progenitors to maintain homeostasis of the Drosophila intestine

“…1 flies. As we found them to be comparable (suppl Fig.2, and in accordance with (Sarpal et al, 2019), we next set out to establish if the increased gut width resulted from an increase in cell numbers. Guts were processed for electron microscopy (fig.2A) or immunofluorescence (fig.2B) and cells were counted in cross sections.…”

Hippo‐Yap/Taz signaling: Complex network interactions and impact in epithelial cell behavior

“…Junctional and polarity complexes have all been linked with cell density‐dependent regulation of Hippo‐Yap signaling (Benham‐Pyle, Pruitt, & Nelson, ; Delanoë‐Ayari, AL Kurdi, Vallade, Gulino‐debrac, & Riveline, ; Gottardi, Wong, & Gumbiner, ; N.‐G. Kim, Koh, Chen, & Gumbiner, ; Perrais, Chen, Perez‐Moreno, & Gumbiner, ; Sarpal, Yan, Kazakova, Sheppard, & Tepass, ; Schlegelmilch et al, ; Silvis et al, ; Szymaniak, Mahoney, Cardoso, & Varelas, ; Varelas et al, ; C.‐C. Yang, Graves, et al, ; Zhou et al, ).…”

“…Junctional and polarity complexes have all been linked with cell density-dependent regulation of Hippo-Yap signaling (Benham-Pyle, Pruitt, & Nelson, 2015; Delanoë-Ayari, AL Kurdi, Vallade, Gulino-debrac, & Riveline, 2004;Gottardi, Wong, & Gumbiner, 2001;N.-G. Kim, Koh, Chen, & Gumbiner, 2011;Perrais, Chen, Perez-Moreno, & Gumbiner, 2007;Sarpal, Yan, Kazakova, Sheppard, & Tepass, 2019;Schlegelmilch et al, 2011;Silvis et al, 2011;Varelas et al, 2010;C.-C. Yang, Graves, et al, 2015;Zhou et al, 2018). E-cadherin and β-catenin are crucial for contact inhibition such that their depletion stimulates cell proliferation.…”

“…α-Catenin also interacts with Ajuba LIM protein (Drosophila Jub), which, through Ajuba-Lats1/2 interaction, inhibits Lats1/2 activity and causes Yap nuclear localization in an actin cytoskeletal tension-dependent fashion. Notably, Ajuba is a target of Yap in bronchiolar epithelial cells, thus establishing a positive feedback loop that reinforces Yap nuclear localization (Das Thakur et al, 2010;Hirata, Samsonov, & Sokabe, 2017;Lange et al, 2015;Rauskolb, Sun, Sun, Pan, & Irvine, 2014;Sarpal et al, 2019;Schlegelmilch et al, 2011;Silvis et al, 2011;B. Yang, Sheetz, et al, 2015).…”