Defining the Protein–Protein Interaction Network of the Human Hippo Pathway

Abstract

The Hippo pathway, which is conserved from Drosophila to mammals, has been recognized as a tumor suppressor signaling pathway governing cell proliferation and apoptosis, two key events involved in organ size control and tumorigenesis. Although several upstream regulators, the conserved kinase cascade and key downstream effectors including nuclear transcriptional factors have been defined, the global organization of this signaling pathway is not been fully understood. Thus, we conducted a proteomic analysis of human Hippo pathway, which revealed the involvement of an extensive protein-protein interaction network in this pathway. The mass spectrometry data were deposited to ProteomeXchange with identifier PXD000415. Our data suggest that 550 interactions within 343 unique protein components constitute the central protein-protein interaction landscape of human Hippo pathway. Our study provides a glimpse into the global organization of Hippo pathway, reveals previously unknown interactions within this pathway, and uncovers new potential components involved in the regulation of this pathway. Understanding these interactions will help us further dissect the Hippo signaling-pathway and extend our knowledge of organ size control. Molecular &

The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease

“…Most upstream components in the Hippo pathway are conserved in mammals, including the MST1 and MST2 kinases (homologs of Hippo, also known as STK4 and STK3), SAV1 (a homolog of Salvador, also known as WW45), and MOB1A and MOB1B (homologs of Mob). However, as is the case with flies, numerous studies, including recent mass spectrometry-based proteomic studies Wang et al, 2013), have extended the effectors of the pathway, many of which have not yet been dissected in detail.…”

Discovering the Hippo pathway protein-protein interactome

“…Three recent reports now describe proteomic studies uncovering extensive protein-protein interaction networks that connect the Hippo pathway to proteins involved in other signaling pathways and processes [5][6][7]. All three papers used many of the known Hippo pathway components as baits to identify interacting proteins by affinity purification and mass spectrometry (AP-MS) in cultured cells.…”

“…They then tested the function of these proteins by RNAi knock-down and found that 102 of them affected the transcriptional activity of Yorkie. The two other studies by Wang et al [6] and Couzens et al, [7] from the groups of Junjie Chen and Anne-Claude Gingras, characterized the protein-protein interaction network of the human Hippo pathway and identified high-confidence networks of 343 and 445 proteins, respectively. All three studies rediscovered many of the known interactions between pathway components.…”

“…Wang et al [6] identified a novel regulator of YAP, the coiled-coil domain-containing protein 85C (CCDC85C) that also localizes to tight junctions [8]. Similar to AMOT, CCDC85C binds to the WW domains of YAP and induces its nuclear export, thereby inhibiting YAP activity [6].…”

“…Kwon et al now expand the repertoire of positive regulators: For example, they identified the fly homologs of NUDT21 (CPSF5) and CPSF6 [5] that were also identified as YAP interactors by Wang and colleagues [6]. NUDT21 and CPSF6 are involved in the cleavage and polyadenylation of mRNAs [9,10], although how they regulate YAP/Yorkie remains to be investigated.…”