CST Guide:

Section I: Research Areas
chapter 06: Development and differentiation
Hippo Signaling
Adherens Junction Tight Junction
Crb
ZO-2
YAP/TAZ
AMOT
YAP/TAZ
AMOT
β-TrCP
FRMD
Merlin
KIBRA
SIK1-3
α-catenin
Mst1/2
LKB1
14-3-3 SAV1
MARK4
YAP
14-3-3
YAP
RASSF
Ajuba
CK1
Merlin
CD44
FAT4
LATS1/2
YAP/TAZ
TAOK-1-3
MOB1
GPCR Signaling
PP2A
F-actin
ITCH
PP1
Gα 12/13
ASPP2
Gα q/11
Gα i/o
AMOT
Gα s
Mechanical Signaling
Rho
Hedgehog Signaling
PKA
SUFU
GLI 1/2/3
SUFU
β−TrCP
CK1
GLI 1/2/3
GSK-3β
Proteasome
Repressor GLI 3-R
no transcription of
target genes
Cytoplasm
KIF7
Primary
Cilium
GLI 1/2/3
Microtubules
SMO
GLI 1/2 Degradation
Off-State
Skn
PTCH1
GLI 3-R
SCUBE2
CDON/BOC
Nucleus
Hh
HhN
DISP1
PTCH2
Primary
Cilium
ER/Golgi
HhN
Microtubules
SUFU
GLI 1/2/3
GLI 1/2-Act
Activator
KCTD11
Cyclin D, Cyclin E,
Myc, GLI1, PTCH1,
PTCH2, Hhip1
Cytoplasm
KIF7
Hh Secreting Cell
Gα i
β-Arrestin
SMO
On-State
PTCH1
GLI 1/2-Act
Mammalian
Ligands:
Ihh
Dhh
Shh
CDON/BOC
Nucleus
Hhip1 GAS1
The evolutionarily conserved Hedgehog (Hh) pathway is essential for normal embryonic development and plays critical roles in adult tissue maintenance, renewal and regeneration.
Secreted Hh proteins act in a concentration- and time-dependent manner to initiate a series of cellular responses that range from survival and proliferation to cell fate
specification and differentiation.
HhN
VGL4
TEAD1-4
WBP2
YAP/TAZ
TEAD1-4
YAP/TAZ
Smad
YAP/TAZ
p73
YAP/TAZ
RUNX
Nucleus
Transcription
Cytoplasm
Hippo signaling is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, apoptosis, and stem cell self renewal. In addition, dysregulation
of the Hippo pathway contributes to cancer development. Core to the Hippo pathway is a kinase cascade, wherein Mst1/2 (ortholog of Drosophila Hippo) kinases and SAV1
form a complex to phosphorylate and activate LATS1/2. LATS1/2 kinases in turn phosphorylate and inhibit the transcription co-activators YAP and TAZ, two major downstream
effectors of the Hippo pathway. When dephosphorylated, YAP/TAZ translocate into the nucleus and interact with TEAD1-4 and other transcription factors to induce expression
of genes that promote cell proliferation and inhibit apoptosis. The Hippo pathway is involved in cell contact inhibition, and its activity is regulated at multiple levels: Mst1/2 and
LATS1/2 are regulated by upstream molecules such as Merlin, KIBRA, RASSFs, and Ajuba; 14-3-3, α-catenin, AMOT, and ZO-2 retain YAP/TAZ in the cytoplasm, adherens
junctions, or tight junctions by binding; Mst1/2 and YAP/TAZ phosphorylation and activity are modulated by phosphatases; Lats1/2 and YAP/TAZ stability are regulated by
protein ubiquitination; and LATS1/2 activity is also regulated by the cytoskeleton. Despite extensive study of the Hippo pathway in the past decade, the exact nature of extracellular
signals and membrane receptors regulating the Hippo pathway remains elusive.
Select Reviews:
Badouel, C. and McNeill, H. (2011) Cell 145, 484–484. • Genevet, A. and Tapon, N. (2011) Biochem. J. 436, 213–224. • O’Hayre, M., Degese, M.S., and Gutkind, J.S.
(2014) Curr. Opin. Cell Biol. 27, 126–135. • Pan, D. (2010) Dev. Cell 19, 491–505. • Sudol, M. and Harvey, K.F. (2010) Trends Biochem. Sci. 35, 627–633. • Yu, F.X.
and Guan, K.L. (2013) Genes Dev. 27, 355–371. • Zhao, B., Li, L., Lei, Q., and Guan, K.L. (2010) Genes Dev. 24, 862–874. • Zhao, B., Tumaneng, K., and Guan, K.L.
(2011) Nat. Cell Biol. 13, 877–883.
Proper levels of Hh signaling require the regulated production, processing, secretion and trafficking of Hh ligands– in mammals this includes Sonic (Shh), Indian (Ihh) and
Desert (Dhh). All Hh ligands are synthesized as precursor proteins that undergo autocatalytic cleavage and concomitant cholesterol modification at the carboxy terminus
and palmitoylation at the amino terminus, resulting in a secreted, dually-lipidated protein. Hh ligands are released from the cell surface through the combined actions of
Dispatched and Scube2, and subsequently trafficked over multiple cells through interactions with the cell surface proteins LRP2 and the Glypican family of heparan sulfate
proteoglycans (GPC1-6).
Hh proteins initiate signaling through binding to the canonical receptor Patched (PTCH1) and to the co-receptors GAS1, CDON and BOC. Hh binding to PTCH1 results in derepression
of the GPCR-like protein Smoothened (SMO) that results in SMO accumulation in cilia and phosphorylation of its cytoplasmic tail. SMO mediates downstream signal
transduction that includes dissociation of GLI proteins (the transcriptional effectors of the Hh pathway) from kinesin-family protein, Kif7, and the key intracellular Hh pathway
regulator SUFU.
GLI proteins also traffic through cilia and in the absence of Hh signaling are sequestered by SUFU and Kif7, allowing for GLI phosphorylation by PKA, GSK3β and CK1, and
subsequent processing into transcriptional repressors (through cleavage of the carboxy-terminus) or targeting for degradation (mediated by the E3 ubiquitin ligase β-TrCP). In
response to activation of Hh signaling, GLI proteins are differentially phopshorylated and processed into transcriptional activators that induce expression of Hh target genes,
many of which are components of the pathway (e.g. PTCH1 and GLI1). Feedback mechanisms include the induction of Hh pathway antagonists (PTCH1, PTCH2 and Hhip1)
that interfere with Hh ligand function, and GLI protein degradation mediated by the E3 ubiquitin ligase adaptor protein, SPOP.
In addition to vital roles during normal embryonic development and adult tissue homeostasis, aberrant Hh signaling is responsible for the initiation of a growing number of
cancers including, classically, basal cell carcinoma, medulloblastoma, and rhabdomyosarcoma; more recently overactive Hh signaling has been implicated in pancreatic,
lung, prostate, ovarian, and breast cancer. Thus, understanding the mechanisms that control Hh pathway activity will inform the development of novel therapeutics to treat a
growing number of Hh-driven pathologies.
Select Reviews:
Beachy, P.A., Hymowitz, S.G., Lazarus, R.A., Leahy, D.J., and Siebold, C. (2010) Genes Dev. 24, 2001–2012. • Eaton, S. (2008) Nat. Rev. Mol. Cell Biol. 9, 437–445. •
Hui, C.C. and Angers, S. (2011) Annu. Rev. Cell Dev. Biol. 27, 513–537. • Ingham, P.W., Nakano, Y., and Seger, C. (2011) Rev. Genet. 12, 393–406. • Ng, J.M. and
Curran, T. (2011) Nat. Rev. Cancer 11, 493–501. • Wilson, C.W. and Chuang, P.T. (2010) Development 137, 2079–2094. • Teglund, S., and Toftgard, R. (2010) Biochim.
Biophys. Acta. 1805, 181–208. • Briscoe, J., and Therond, P.P. (2013) Nat. Rev. Mol. Cell Biol. 14, 416–429. • Goetz, S.C., and Anderson, K.V. (2010) Nat. Rev. Genet.
11, 331–344. • Falkenstein, K.N., and Vokes, S.A. (2014) Semin. Cell Dev. Biol. 33, 73–80.
© 2010–2015 Cell Signaling Technology, Inc. • We would like to thank Prof. Kun-Liang Guan, University of California, San Diego, CA for reviewing this diagram.
162 For Research Use Only. Not For Use in Diagnostic Procedures. See pages 302 & 303 for Pathway Diagrams, Application, and Reactivity keys.
© 2006–2015 Cell Signaling Technology, Inc. • We would like to thank Prof. Hans Widlund, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, for reviewing this diagram.
www.cellsignal.com/cstpathways 163