Transcript Hippo pathway

Hippo pathway
Orkhon Tsogtbaatar, ID: 20088110
April 18, 2012
Hippo pathway
 discovered as a signal pathway that regulates
organ size in Drosophila melanogaster.
 known as the Salvador/Warts/Hippo (SWH) pathway
 Its key signaling component — the protein kinase
Hippo (Hpo).
 Mutations in this gene lead to tissue overgrowth, or
“hippopotamus”-like phenotype
Adult fly
Mice liver at 2 months
Hippo pathway
Composed of three components:
 1) cell surface upstream regulators (including cell
adhesion molecules and cell polarity complexes;
 2) a kinase cascade (comprising two Ser-Thr
kinases with regulators and adaptors)
 3) a downstream target, a transcription coactivator
(transcription of cell proliferation-promoting and
anti-apoptotic genes).
J. Biochem. 2011; 149(4):361-379
Fundamental questions
What mechanisms are used to regulate
growth to form organs of particular size?
What mechanisms are used to tell the
proliferating cells that the certain organs
has reached its original intended size and
that it is time to exit the cell cycle?
Warts/large tumor suppressor (wts/lats)
lats mutant phenotypes
Warts/large tumor suppressor
(wts/lats)
 A kinase of the nuclear
Dbf-2-related (NDR)
family
Loss of hpo results in tissue
overgrowth
3rd instar eye disc
pupal
eye
hpo regulates cell proliferation and
apoptosis
hpo encodes a protein kinase
Genetic interaction among hpo,
sav, and wts
GMR-hpo+wts
100% early
pupal lethal
Hpo/Sav interaction promotes
Wts phosphorylation
Sav facilitates the
phosphorylation
of Wts by Hpo
Hpo binds and
phosphorylates
Sav
Hpo - Sav - Wts
Regulate cell proliferation
mats required to restrict cell proliferation and promote apoptosis
mats genetically interacts with wts
※ Mats and Wts
synergistically interact to
control cell proliferation
and apoptosis
Hpo kinase cascade
※ Loss-of-function mutations in
any of these genes result in
overgrowth due to increased
cell proliferation and growth,
and reduced cell death.
Overexpression of yki drives outgrowth
Overexpression of yki promotes cell
proliferation and inhibits apoptosis
 Activation of yki leads to
increased cell proliferation
and decreased apoptosis
 Activation of yki leads to
increased transcription of
diap1 and CycE
The Hpo signaling pathway
antagonizes the transcriptional
coactivator activity of Yki
yki is genetically epistatic
to hpo, sav, and wts
※ Yki is a target of
Wts in Hpo pathway
Upstream regulators
※ merlin and expanded regulate tissue size
Merlin and Expanded act upstream of
Hippo and Warts
fat (ft) encodes atypical cadherin,
a transmembrane protein that is
known to control cell proliferation
※ ft restricts organ size by modulating
activity of the Sav/Wts/Hpo pathway
The Sav/Wts/Hpo pathway
14-3-3
Schematic model of the Hippo
signaling network
(Diap1, bantam,
cycE, dmyc…)
Cell cycle promoting and antiapoptotic gene transcription
The hippo signaling network in
Drosophila and Mammals
normal
> yki
> YAP
Summary
 The pathway negatively regulates the coactivator to restrict
cell proliferation and to promote cell death.
 Thus, the pathway prevents tissue overgrowth and
tumourigenesis.
 A dysfunction of the pathway is frequently detected in
human cancers and correlates with poor prognosis.
 Recent works indicated that the Hippo pathway plays an
important role in tissue homoeostasis through the regulation
of stem cells, cell differentiation and tissue regeneration.
Future Study
 How the activity of the Hpo kinase is controlled by
upstream regullators?
 How the levels of Wts protein are controlleed by
Dachs and Zyx?
 How all of the different inputs into the pathway are
related to each other?
 How these diverse inputs are integrated to achieve
appropriate levels of Yki activity?
 How the Hpo pathway is integrated with other growth
control pathways?
Thank you for
attention!
Thank you for
attention!
Thank you for
attention!
Drosophila melanogaster, a Fruit Fly