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The Hippo Pathway. Hippo pathway Signaling components Over-expression & knockout studies Role in cancer Regulation. A good review: Pan D. Hippo signaling in organ size control. Genes Dev. 2007 Apr 15;21(8):886-97. Wu S, Huang J, Dong J, Pan D. Cell. 2003 Aug 22;114(4):445-56.

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The Hippo Pathway


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slide2

Hippo pathway

Signaling components

Over-expression & knockout studies

Role in cancer

Regulation

A good review:

Pan D.

Hippo signaling in organ size control.

Genes Dev. 2007 Apr 15;21(8):886-97.

slide3

Wu S, Huang J, Dong J, Pan D.

Cell. 2003 Aug 22;114(4):445-56.

Harvey KF, Pfleger CM,

Hariharan IK.

Cell. 2003 Aug 22;114(4):457-67.

Rescue

mammalian

Hippo

slide4

Hippo pathway

Described about 5 years ago in flies

- various mammalian components identified previously

Regulates growth, differentiation, cell death

Kinase cascade regulates P-state of transcription factor(s)

- negative regulation

slide5

Hippo & Warts

kinases

Salvador & Mats

co-factors

Yorkie

slide6

Focus on Transcription Factor

Transcriptionally activates various growth

& anti-apoptosis genes

Mammalian homolog Yap

- identified P-site Ser127

- S127A no longer sequestered by 14-3-3

- constitutively active

slide7

Dong J, et al.

Cell. 2007 Sep 21;130(6):1120-33.

slide8

Dong J, et al.

Cell. 2007 Sep 21;130(6):1120-33.

slide9

Dong J, et al.

Cell. 2007 Sep 21;130(6):1120-33.

slide10

Dong J, et al.

Cell. 2007 Sep 21;130(6):1120-33.

Jo2 Ab

H&E Tunel

BrdU

1 week Dox

(B and C) YAP overexpression drives cell proliferation. Control (B) and ApoE/rtTA-YAP (C) livers after 1 week of Dox exposure were analyzed for BrdU incorporation (red), counterstained with DAPI (blue).(D–H) YAP overexpression confers potent resistance to apoptosis. Control and ApoE/rtTA-YAP littermates were kept on Dox for 1 week, injected with Jo-2, and analyzed 3 hr postinjection by H&E staining (D and E), TUNEL (F and G), and western blotting for cell death markers (H). Note the widespread hemorrhage (asterisk) and apoptotic nuclei (arrowhead) in the control (D), but not the transgenic livers (E). Also note the extensive TUNEL staining in the control (F), but not the transgenic livers (G). In (H), cleavage of caspase-3 (Casp3) and PARP was detected in the control, but not the transgenic, livers (arrowhead marks the cleaved PARP product). Three animals were analyzed for each genotype.(I) RNAi knockdown of BIRC5/survivin reduces the transforming activity of YAP. Left: western blots showing increased BIRC5/survivin expression in YAP-HPNE cells compared to mock transfected cells, and the knockdown of BIRC5/survivin expression in YAP-HPNE cells stably expressing BIRC5/survivin shRNA. Right: soft agar assay showing anchorage-independent growth of YAP-HPNE cells, a feature that is not observed in the mock-transfected HPNE cells. Note that YAP-HPNE cells stably expressing BIRC5/survivin shRNA formed reduced numbers of colonies.

slide11

3 months dox

(at birth)

8 weeks dox

(at 3 weeks)

(A) Liver from an ApoE/rtTA-YAP mouse raised on Dox for 8 weeks, starting at 3 weeks after birth. Note the presence of discrete nodules scattered throughout the liver (arrowheads).

(B) Liver from an ApoE/rtTA-YAP mouse raised on Dox for 3 months, starting at birth. Note the widespread development of HCC throughout the liver.

(C–E) Histolopathologic examination of murine liver nodules reveals characteristics of hepatocellular carcinoma. Mice were fed Dox-water as in (A). (C) shows cellular pleiomorphism of YAP-induced HCC, with a large cell (arrow) surrounded by smaller cells. (D) shows loss of cytoplasmic staining (arrows), or the so called “clear cell change.” (E) shows expanded hepatic plates. A reticulin stain highlights the edges of the hepatic plates (indicated by parallel lines), which are wider in HCC than the typical 1 to 2 cells in a nonneoplastic liver.

(F) Survival curves of control (Non-Tg) and ApoE/rtTA-YAP (Tg) littermates raised on Dox, starting at 3 or 8 weeks of age as indicated.

Dong J, et al.

Cell. 2007 Sep 21;130(6):1120-33.

slide13

5 weeks

5 weeks

Camargo FD, et al.

Curr Biol. 2007 Dec 4;17(23):2054-60

(A) Schematic representation of liver-specific doxycycline-inducible YAP1 allele. The tetracycline transactivator (tTA) expression is driven by the liver activator protein (LAP) promoter. A tetracycline regulatable allele of YAP1-S127A was integrated downstream of the Col1A1 locus.

(B) Gross morphology of the liver in control and YAP1 transgenic mice induced for 5 weeks (top) and mice induced for 5 weeks followed by reversal of YAP1 activation for another 5 weeks (bottom).

slide14

5 days

post-induction

loss of

differentiated

cells

periodic

acid-Schiff-

lose goblet

cells

Hes - only in

progenitors

Rosa26 rtTA

- ubiquitous

Camargo FD, et al.

Curr Biol. 2007 Dec 4;17(23):2054-60

slide15

Camargo FD, et al.

Curr Biol. 2007 Dec 4;17(23):2054-60

slide16

Relevant role in human cancer?

Screen CGH - hits on chromosome 9

systenic to human 11q22 amplicon

- common in diverse human tumors

slide17

1 - Met

2 - Yap

3 - many genes

Brca flox/-, p53 +/-, MMTC-Cre

Overholtzer M, et al.

Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12405-10.

slide18

Overholtzer M, et al.

Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12405-10.

slide19

Overholtzer M, et al.

Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12405-10.

slide20

Zhang J, Smolen GA, Haber DA.

Cancer Res. 2008 Apr 15;68(8):2789-94.

slide21

Zhang J, Smolen GA, Haber DA.

Cancer Res. 2008 Apr 15;68(8):2789-94.

slide23

WW45 epidermis e17.5

Lee JH, et al.

EMBO J. 2008 Apr 23;27(8):1231-42.

slide24

WW45 intestinal epithelium

Lee JH, et al.

EMBO J. 2008 Apr 23;27(8):1231-42.

slide25

Lee JH, et al.

EMBO J. 2008 Apr 23;27(8):1231-42.

slide27

Hippo pathway

Regulated by neighboring cells

- mediates contact inhibition

Inputs still obscure

Other means of regulation…

slide28

Fat

proto-cadherin

Expanded

&

Merlin

FERM domain

mammalian homologs

for all components

slide29

Cell Density Regulation

Zhao B, et al.

Genes Dev. 2007 Nov 1;21(21):2747-61.

slide30

Merlin

Zhao B, et al.

Genes Dev. 2007 Nov 1;21(21):2747-61.

slide32

Katagiri, et al.

Nat Immunol. 2006 Sep;7(9):919-28.

slide33

Katagiri, et al.

Nat Immunol. 2006 Sep;7(9):919-28.

slide34

Katagiri, et al.

Nat Immunol. 2006 Sep;7(9):919-28.

slide35

ICAM coated surface, CXCL12 stimulation

Katagiri, et al.

Nat Immunol. 2006 Sep;7(9):919-28.

slide36

ICAM coated surface, CXCL12 stimulation

Katagiri, et al.

Nat Immunol. 2006 Sep;7(9):919-28.

slide38

Matallanas, et al.

Mol Cell. 2007 Sep 21;27(6):962-75.

slide40

Lei, et al.

Mol Cell Biol. 2008 Apr;28(7):2426-36.

slide41

Lei, et al.

Mol Cell Biol. 2008 Apr;28(7):2426-36.

slide42

Lei, et al.

Mol Cell Biol. 2008 Apr;28(7):2426-36.