Roles of Membrane and Vesicular Traffic in Regulation of the Hippo Pathway

Abstract

The Hippo pathway is a well conserved signaling cascade that modulates cell proliferation and survival in response to external cues such as cell:cell contact, injury, and nutritional status. Models of the Hippo pathway have evolved from a series of genetic interactions defined in the fruit fly Drosophila melanogaster into a complex series of biochemical mechanisms in which transmembrane and cytoskeletal proteins modulate cytoplasmic phosphatase and kinase activities that converge on the serine/threonine kinase Warts (Wts) to regulate nuclear entry of the co-activator protein Yorkie (Yki; vertebrate Yap1). This pathway is well conserved in human cells and broadly implicated in cancer. Progress in understanding biochemical events within the Hippo pathway highlights a need for improved understanding of the cell biological contexts in which these molecular interactions occur. A significant body of data linking Hippo signaling to membranes and proteins involved in intracellular membrane trafficking raise the possibility that some molecular regulatory events occur on the cytoplasmic face of vesicles. In Drosophila, a Yki-vesicle link was solidified by discoveries that cytoplasmic Yki concentrates at late-endosomes and physically interacts with two endosomal adaptor proteins, Myopic (Mop) and Leash. These two proteins are required for Yki to transit the endolysosomal pathway and be turned over in lysosomes. Molecules involved in recruiting and tethering Yki along this endosomal route are not defined but are predicted to play key roles in regulating Yki levels and thus Hipporesponsiveness of cells. As Wts is recruited to the apical membrane by upstream Hippo components, endosomal internalization could also affect complexes involved in Yki phosphorylation events that alter nucleocytoplasmic shuttling. Recent work has revealed an unexpected, non-transcriptional role of membrane-associated Yki in triggering actinomyosin contractility via the myosin-regulatory light chain Spaghetti squash (Sqh). How Yki interacts with the membrane and controls Sqh is unclear, but this mechanism represents a novel regulatory mechanism based on induced localization of Yki to a specific membrane compartment. These and other data will be discussed as we review data linking Yki to membrane and vesicular traffic in development and homeostasis and speculate on missing elements of these membrane-linked Yki regulatory mechanisms.

α-Arrestin ARRDC3 tumor suppressor function is linked to GPCR-induced TAZ activation and breast cancer metastasis

“…ARRDC3 suppresses GPCR-stimulated Hippo signaling by sequestering TAZ in the cytoplasm, thereby preventing gene induction, migration and metastasis of TNBC A previous study in Drosophila reported that Leash, a homolog of ARRDC3, interacts with Yorkie, the homolog of YAP and TAZ, and inhibits Hippo signaling by facilitating Yorkie degradation (Kwon et al, 2013;Verghese and Moberg, 2020). This discovery gave credence to the idea that mammalian ARRDC3 might regulate Hippo signaling through interactions with YAP and TAZ.…”

Myotubularin functions through actomyosin to interact with the Hippo pathway

“…It is worth mentioning that previous studies have suggested critical roles of intracellular vesicular trafficking in activating Hippo signaling at the plasma membrane (Verghese & Moberg, 2019). Studies in mice also indicated a critical role of Rab11 in suppressing Yap activity by maintaining LATS kinase activity and YAP localization at adherens junctions (D'Agostino et al , 2019; Goswami et al , 2021).…”

Relationship between Yes-Associated Protein 1 and Prognosis of Digestive System Neoplasm: Quantitative Analysis and Bioinformatics Analysis Based on 4023 Patients

“…YAP1 is the main effector downstream of the Hippo signaling pathway. It is a multifunctional intracellular connexin and transcription coactivator, which can have effects on many aspects of human development, growth, DNA repair, and endogenous homeostasis [ 51 , 52 ]. The abnormal expression of YAP1 is associated with the proliferation and invasion of various tumor cells [ 53 , 54 ].…”