Cellular and Molecular Life Sciences (2018) 75:2303–2319
Regulation of the Hippo pathway in cancer biology
· So Yeon Park
· Hyun Woo Park
Received: 20 November 2017 / Revised: 17 March 2018 / Accepted: 22 March 2018 / Published online: 30 March 2018
© Springer International Publishing AG, part of Springer Nature 2018
The Hippo tumor suppressor pathway, which is well conserved from Drosophila to humans, has emerged as the master regu-
lator of organ size, as well as major cellular properties, such as cell proliferation, survival, stemness, and tissue homeostasis.
The biological signiﬁcance and deregulation of the Hippo pathway in tumorigenesis have received a surge of interest in the
past decade. In the current review, we present the major discoveries that made substantial contributions to our understanding
of the Hippo pathway and discuss how Hippo pathway components contribute to cellular signaling, physiology, and their
potential implications in anticancer therapeutics.
Keywords Hippo pathway · YAP/TAZ · TEAD · Cancer · Therapeutic target
Overview of the Hippo pathway
The core Hippo components in Drosophila
Since it was ﬁrst established as a genetic model by Thomas
Hunt Morgan, Drosophila melanogaster has made a large
contribution to our understanding of metazoan develop-
ment . The genetic mosaic screening of Drosophila using
tissue-speciﬁc loss-of-function assays by the ﬂippase/FRT
system is a powerful tool to investigate genetic pathways .
Surprisingly, this led to the discovery of almost all compo-
nents of the Hippo tumor suppressor pathway in experiments
designed to identify growth suppressors. Gene inactivation
in this pathway resulted in massive tissue overgrowth in the
developing eyes or wings. In 1995, two studies discovered
that homozygous loss of Warts (Wts), which encodes a
nuclear Dbf-2-related (NDR) family Ser/Thr kinase, caused
large outgrowth of multiple tissues in Drosophila [3, 4].
These initial ﬁndings indicated that Wts regulates tissue
growth and functions as a tumor suppressor gene. Following
the discovery of Warts, Hariharan, Halder, and collabora-
tors reported that Salvador (Sav; also known as Shar-Pei),
a WW domain-containing protein, genetically and physi-
cally interacts with Wts and that a Sav mutant clone showed
excess interommatidial cells in Drosophila eye development
via elevated cyclin E-induced cell cycle progression [5, 6].
Moreover, Sav-deﬁcient cells induced DIAP1 (Drosophila
inhibitor of apoptosis protein 1), which attenuates apopto-
sis by inhibiting caspase, resulting in cell proliferation and
organ growth. These results suggested that Wts–Sav restrain
massive cell growth during development and may have criti-
cal roles in tumor suppression.
Cellular andMolecular Life Sciences
* Hyun Woo Park
Department of Biochemistry, College of Life Science
and Biotechnology, Yonsei University, Seoul 03722,
Republic of Korea