Enigma proteins regulate YAP mechanotransduction

Abstract

Human cells can sense mechanical stress acting upon integrin adhesions and respond by sending the YAP (also known as YAP1) and TAZ (also known as WWTR1) transcriptional co-activators to the nucleus to drive TEAD-dependent transcription of target genes. How integrin signaling activates YAP remains unclear. Here, we show that integrin-mediated mechanotransduction requires the Enigma and Enigma-like proteins (PDLIM7 and PDLIM5, respectively; denoted for the family of PDZ and LIM domain-containing proteins). YAP binds to PDLIM5 and PDLIM7 (hereafter PDLIM5/7) via its C-terminal PDZ-binding motif (PBM), which is essential for full nuclear localization and activity of YAP. Accordingly, silencing of PDLIM5/7 expression reduces YAP nuclear localization, tyrosine phosphorylation and transcriptional activity. The PDLIM5/7 proteins are recruited from the cytoplasm to integrin adhesions and F-actin stress fibers in response to force by binding directly to the key stress fiber component α-actinin. Thus, forces acting on integrins recruit Enigma family proteins to trigger YAP activation during mechanotransduction..

Dysfunctional Mechanotransduction through the YAP/TAZ/Hippo Pathway as a Feature of Chronic Disease

“…Although YAP is cytoplasmic at high cell density, the loss of cell contact with neighbouring cells or cell spreading results in YAP translocation to the nucleus. The expansion of cell contacts spreading over their basal substrate, the strength of the substrate and resulting mechanical tension are the key determinants of subcellular YAP localization in response to cell density [11,15,16]. Mechanotransduction affects YAP both independently of the canonical Hippo signalling pathway and with the involvement of key Hippo signalling pathway kinases MST and LATS.…”

Hippo signalling during development

“…The exact molecular mechanism by which Talin conformational changes lead to YAP activation is currently unknown, but they could promote focal adhesion signalling. Supporting this hypothesis is the myriad of focal adhesion signalling molecules, such as Focal Adhesion Kinase (FAK) (Kim and Gumbiner, 2015), Integrin-Linked Kinase (ILK) (Serrano et al, 2013), the PDZ and LIM Domain Containing proteins PDLIM5 (Enigma-like)/PDLIM7 (Enigma) (Elbediwy et al, 2018), and Src-family tyrosine kinases (Kim and Gumbiner, 2015), which have all been linked to YAP regulation. Most of these molecules promote YAP activity; for example, Src has been suggested to both directly [via phosphorylation of the C-terminal region of YAP (Li et al, 2016)], and indirectly [by inhibiting Nf2 or LATS (Fan et al, 2013;Kim and Gumbiner, 2015;Si et al, 2017)] promote YAP nuclear localisation.…”

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

“…[ 179 ] Tumor cells interact with the ECM via Integrins, which respond to ligand binding and mechanical stress by signaling through FAK and SRC family kinases [ 180–182 ] to inhibit Hippo signaling and activate YAP/TAZ. [ 31,61,183‐199 ] SRC family kinases appear to act primarily by direct tyrosine phosphorylation of LATS1, but can also directly phosphorylate YAP/TAZ. [ 30,31,61,183‐199 ] Importantly, there is extensive signaling cross‐talk between Integrin‐SRC signaling and Growth factor‐PI3K‐Akt signaling.…”

“…[ 31,61,183‐199 ] SRC family kinases appear to act primarily by direct tyrosine phosphorylation of LATS1, but can also directly phosphorylate YAP/TAZ. [ 30,31,61,183‐199 ] Importantly, there is extensive signaling cross‐talk between Integrin‐SRC signaling and Growth factor‐PI3K‐Akt signaling. [ 200–206 ] In addition, mechanotransduction via Integrin‐SRC signaling also promotes formation of focal adhesions and stress fibers, a process involving increased Rho GTPase mediated actomyosin contractility.…”