Abstract
Yes-associated protein (YAP) signaling has emerged as a crucial pathway in several normal and pathological processes. Although the main upstream effectors that regulate its activity have been extensively studied, the role of the endosomal system has been far less characterized. Here, we identified the late endosomal/lysosomal adaptor MAPK and mTOR activator (LAMTOR) complex as an important regulator of YAP signaling in a preosteoblast cell line. We found that p18/LAMTOR1-mediated peripheral positioning of late endosomes allows delivery of SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) to the plasma membrane and promotes activation of an SRC-dependent signaling cascade that controls YAP nuclear shuttling. Moreover, β1 integrin engagement and mechano-sensitive cues, such as external stiffness and related cell contractility, controlled LAMTOR targeting to the cell periphery and thereby late endosome recycling and had a major impact on YAP signaling. Our findings identify the late endosome recycling pathway as a key mechanism that controls YAP activity and explains YAP mechano-sensitivity.
Highlights
Yes-associated protein (YAP) signaling has emerged as a crucial pathway in several normal and pathological processes
After transduction of viral particles that express p18/LAMTOR1 fused to GFP (p18-GFP) and RFP-VASP in parental (b1f/f) preosteoblasts and in preosteoblasts that lack the b1 integrin subunit (b12/2) [25], we observed that p18/LAMTOR1-positive vesicles were at the cell periphery in control cells
YAP and transcriptional co-activator with PDZ-binding motif (TAZ) are both regulated by mechanical cues, and so far, little is known about their differential regulation
Summary
Yes-associated protein (YAP) signaling has emerged as a crucial pathway in several normal and pathological processes. LAMTOR controls SRC-dependent YAP nuclear translocation shuttling and for LE targeting to FAs. we found that b1 integrins, through integrin-linked protein kinase (ILK), allows the organization of a functional microtubule network that transports SRC-positive LEs to the cell periphery, a crucial process in the regulation of YAP nuclear shuttling.
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