Two Hippo signaling modules orchestrate liver size and tumorigenesis.
The Hippo pathway is a central regulator of organ size and tumorigenesis and is commonly depicted as a kinase cascade, with an increasing number of regulatory and adaptor proteins linked to its regulation over recent years. Here, we propose that two Hippo signaling modules, MST1/2-SAV1-WWC1-3 (HPO1) and MAP4K1-7-NF2 (HPO2), together regulate the activity of LATS1/2 kinases and YAP/TAZ transcriptional co-activators. In mouse livers, the genetic inactivation of either HPO1 or HPO2 module results in partial activation of YAP/TAZ, bile duct hyperplasia, and hepatocellular carcinoma (HCC). On the contrary, inactivation of both HPO1 and HPO2 modules results in full activation of YAP/TAZ, rapid development of intrahepatic cholangiocarcinoma (iCCA), and early lethality. Interestingly, HPO1 has a predominant role in regulating organ size. HPO1 inactivation causes a homogenous YAP/TAZ activation and cell proliferation across the whole liver, resulting in a proportional and rapid increase in liver size. Thus, this study has reconstructed the order of the Hippo signaling network and suggests that LATS1/2 and YAP/TAZ activities are finetuned by HPO1 and HPO2 modules to cause different cell fates, organ size changes, and tumorigenesis trajectories.
Pubmed ID: 36919851 RIS Download
Research resources used in this publication
- pSpCas9(BB)-2A-Puro (PX459) V2.0 (RRID:Addgene_62988) (plasmid)
- pSpCas9(BB)-2A-Puro (PX459) V2.0 (RRID:Addgene_62988) (plasmid)
- Goat Anti-Rat IgG (H+L) Antibody, Alexa Fluor ?? 647 Conjugated (RRID:AB_141778) (antibody)
- Goat anti-Rabbit IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 555 (RRID:AB_2535849) (antibody)
- Peroxidase IgG Fraction Monoclonal Mouse Anti-Rabbit IgG, light chain specific (RRID:AB_2339149) (antibody)
- Peroxidase-AffiniPure Goat Anti-Rabbit IgG (H+L) (RRID:AB_2313567) (antibody)
- Peroxidase-AffiniPure Goat Anti-Mouse IgG (H + L) (RRID:AB_10015289) (antibody)
- Keratin, type I; cytokeratin 19 antibody - Kemler, R.; MPI fuer Immunobiologie (RRID:AB_2133570) (antibody)
- LATS1/LATS2 Antibody (RRID:AB_2133375) (antibody)
- Ki67 antibody - Proliferation Marker (RRID:AB_443209) (antibody)
- Cytokeratin 19 antibody [EP1580Y] (RRID:AB_2281020) (antibody)
- WWC2 antibody (RRID:AB_11140331) (antibody)
- STK3 antibody [EP1466Y] (RRID:AB_882734) (antibody)
- Mouse Anti-MST1 Monoclonal Antibody, Unconjugated, Clone 7 (RRID:AB_398365) (antibody)
- Mouse Anti-Hsp90 Monoclonal Antibody, Unconjugated, Clone 68 (RRID:AB_397798) (antibody)
- Anti-WWTR1 antibody produced in rabbit (RRID:AB_1080602) (antibody)
- Mouse Anti-FLAG?? Monoclonal Antibody, Horseradish Peroxidase Conjugated (RRID:AB_439702) (antibody)
- Monoclonal Anti-alpha-Tubulin antibody produced in mouse (RRID:AB_477583) (antibody)
- HNF4α (C11F12) Rabbit mAb (RRID:AB_2295208) (antibody)
- Sox9 (D8G8H) Rabbit mAb #82630 (RRID:AB_2665492) (antibody)
- Recombinant Anti-Striatin 4 antibody [EPR11801] (RRID:AB_2927671) (antibody)
- FAM40A Antibody (RRID:AB_2620839) (antibody)
- Anti-FAM40B antibody produced in rabbit (RRID:AB_1848399) (antibody)
- HGK (D19H10) Rabbit mAb (RRID:AB_10694775) (antibody)
- Phospho-YAP (Ser127) Antibody (RRID:AB_2218913) (antibody)
- YAP/TAZ (D24E4) Rabbit mAb (RRID:AB_10950494) (antibody)
- YAP (D8H1X) XP Rabbit mAb (RRID:AB_2650491) (antibody)
- Phospho-MOB1 (Thr35) (D2F10) Rabbit mAb (RRID:AB_11139998) (antibody)
- SAV1 (D6M6X) Rabbit mAb (RRID:AB_2798176) (antibody)
- MOB1 (E1N9D) (RRID:AB_2783010) (antibody)
- Anti-Mst1, phospho (Thr183) / Mst2, phospho (Thr180) Antibody, Unconjugated (RRID:AB_330269) (antibody)
- Mst1 Antibody (RRID:AB_2144632) (antibody)
- Merlin (D3S3W) Rabbit mAb #12888 (RRID:AB_2650551) (antibody)
- Phospho-LATS1 (Thr1079) (D57D3) Rabbit mAb (RRID:AB_10971635) (antibody)
- Anti-LATS2 (D83D6) Rabbit mAb (RRID:AB_10835233) (antibody)
- LATS1 (C66B5) Rabbit mAb (RRID:AB_2133513) (antibody)
- HA-Tag (C29F4) Rabbit mAb (HRP Conjugate) (RRID:AB_2798368) (antibody)
- Vinculin (E1E9V) XP® (RRID:AB_2728768) (antibody)
- Cyr61 (H-78) (RRID:AB_2088733) (antibody)
Additional research tools detected in this publication
None foundAntibodies used in this publication
- Goat Anti-Rat IgG (H+L) Antibody, Alexa Fluor ?? 647 Conjugated (RRID:AB_141778)
- Goat anti-Rabbit IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 555 (RRID:AB_2535849)
- Peroxidase IgG Fraction Monoclonal Mouse Anti-Rabbit IgG, light chain specific (RRID:AB_2339149)
- Peroxidase-AffiniPure Goat Anti-Rabbit IgG (H+L) (RRID:AB_2313567)
- Peroxidase-AffiniPure Goat Anti-Mouse IgG (H + L) (RRID:AB_10015289)
- Keratin, type I; cytokeratin 19 antibody - Kemler, R.; MPI fuer Immunobiologie (RRID:AB_2133570)
- LATS1/LATS2 Antibody (RRID:AB_2133375)
- Ki67 antibody - Proliferation Marker (RRID:AB_443209)
- Cytokeratin 19 antibody [EP1580Y] (RRID:AB_2281020)
- WWC2 antibody (RRID:AB_11140331)
- STK3 antibody [EP1466Y] (RRID:AB_882734)
- Mouse Anti-MST1 Monoclonal Antibody, Unconjugated, Clone 7 (RRID:AB_398365)
- Mouse Anti-Hsp90 Monoclonal Antibody, Unconjugated, Clone 68 (RRID:AB_397798)
- Anti-WWTR1 antibody produced in rabbit (RRID:AB_1080602)
- Mouse Anti-FLAG?? Monoclonal Antibody, Horseradish Peroxidase Conjugated (RRID:AB_439702)
- Monoclonal Anti-alpha-Tubulin antibody produced in mouse (RRID:AB_477583)
- HNF4α (C11F12) Rabbit mAb (RRID:AB_2295208)
- Sox9 (D8G8H) Rabbit mAb #82630 (RRID:AB_2665492)
- Recombinant Anti-Striatin 4 antibody [EPR11801] (RRID:AB_2927671)
- Anti-FAM40B antibody produced in rabbit (RRID:AB_1848399)
- FAM40A Antibody (RRID:AB_2620839)
- HGK (D19H10) Rabbit mAb (RRID:AB_10694775)
- Phospho-YAP (Ser127) Antibody (RRID:AB_2218913)
- YAP/TAZ (D24E4) Rabbit mAb (RRID:AB_10950494)
- YAP (D8H1X) XP Rabbit mAb (RRID:AB_2650491)
- Phospho-MOB1 (Thr35) (D2F10) Rabbit mAb (RRID:AB_11139998)
- MOB1 (E1N9D) (RRID:AB_2783010)
- SAV1 (D6M6X) Rabbit mAb (RRID:AB_2798176)
- Anti-Mst1, phospho (Thr183) / Mst2, phospho (Thr180) Antibody, Unconjugated (RRID:AB_330269)
- Merlin (D3S3W) Rabbit mAb #12888 (RRID:AB_2650551)
- Mst1 Antibody (RRID:AB_2144632)
- Phospho-LATS1 (Thr1079) (D57D3) Rabbit mAb (RRID:AB_10971635)
- Anti-LATS2 (D83D6) Rabbit mAb (RRID:AB_10835233)
- LATS1 (C66B5) Rabbit mAb (RRID:AB_2133513)
- HA-Tag (C29F4) Rabbit mAb (HRP Conjugate) (RRID:AB_2798368)
- Vinculin (E1E9V) XP® (RRID:AB_2728768)
- Cyr61 (H-78) (RRID:AB_2088733)
Associated grants
NonePublication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This is a list of tools and resources that we have found mentioned in this publication.
Goat Anti-Rat IgG (H+L) Antibody, Alexa Fluor ?? 647 Conjugated (antibody)
RRID:AB_141778
This polyclonal secondary targets IgG (H+L)
View all literature mentionsGoat anti-Rabbit IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 555 (antibody)
RRID:AB_2535849
This polyclonal secondary targets IgG (H+L)
View all literature mentionsPeroxidase IgG Fraction Monoclonal Mouse Anti-Rabbit IgG, light chain specific (antibody)
RRID:AB_2339149
This monoclonal secondary targets IgG, Light Chain Specific
View all literature mentionsPeroxidase-AffiniPure Goat Anti-Rabbit IgG (H+L) (antibody)
RRID:AB_2313567
This polyclonal targets IgG (H+L)
View all literature mentionsPeroxidase-AffiniPure Goat Anti-Mouse IgG (H + L) (antibody)
RRID:AB_10015289
This polyclonal targets IgG (H + L)
View all literature mentionsKeratin, type I; cytokeratin 19 antibody - Kemler, R.; MPI fuer Immunobiologie (antibody)
RRID:AB_2133570
This monoclonal targets Keratin, type I; cytokeratin 19
View all literature mentionsLATS1/LATS2 Antibody (antibody)
RRID:AB_2133375
This unknown targets LATS1/LATS2
View all literature mentionsKi67 antibody - Proliferation Marker (antibody)
RRID:AB_443209
This polyclonal targets Ki67 antibody - Proliferation Marker
View all literature mentionsCytokeratin 19 antibody [EP1580Y] (antibody)
RRID:AB_2281020
This monoclonal targets Human Cytokeratin 19
View all literature mentionsWWC2 antibody (antibody)
RRID:AB_11140331
This polyclonal targets WWC2 antibody
View all literature mentionsSTK3 antibody [EP1466Y] (antibody)
RRID:AB_882734
This monoclonal targets STK3
View all literature mentionsMouse Anti-MST1 Monoclonal Antibody, Unconjugated, Clone 7 (antibody)
RRID:AB_398365
This monoclonal targets MST1
View all literature mentionsMouse Anti-Hsp90 Monoclonal Antibody, Unconjugated, Clone 68 (antibody)
RRID:AB_397798
This monoclonal targets Hsp90
View all literature mentionsAnti-WWTR1 antibody produced in rabbit (antibody)
RRID:AB_1080602
This unknown targets Human WWTR1
View all literature mentionsMouse Anti-FLAG?? Monoclonal Antibody, Horseradish Peroxidase Conjugated (antibody)
RRID:AB_439702
This monoclonal targets FLAG
View all literature mentionsMonoclonal Anti-alpha-Tubulin antibody produced in mouse (antibody)
RRID:AB_477583
This monoclonal targets alpha-Tubulin
View all literature mentionsHNF4α (C11F12) Rabbit mAb (antibody)
RRID:AB_2295208
This monoclonal targets HNF4alpha
View all literature mentionsSox9 (D8G8H) Rabbit mAb #82630 (antibody)
RRID:AB_2665492
This monoclonal targets Sox9
View all literature mentionsRecombinant Anti-Striatin 4 antibody [EPR11801] (antibody)
RRID:AB_2927671
This monoclonal targets Striatin 4
View all literature mentionsAnti-FAM40B antibody produced in rabbit (antibody)
RRID:AB_1848399
This polyclonal targets FAM40B antibody produced in rabbit
View all literature mentionsHGK (D19H10) Rabbit mAb (antibody)
RRID:AB_10694775
This monoclonal targets HGK (D19H10) Rabbit mAb
View all literature mentionsPhospho-YAP (Ser127) Antibody (antibody)
RRID:AB_2218913
This polyclonal targets YAP1
View all literature mentionsYAP/TAZ (D24E4) Rabbit mAb (antibody)
RRID:AB_10950494
This monoclonal targets Monoclonal antibody is produced by immunizing animals with a synthetic peptide corresponding to residues surrounding Asp362 of human TAZ protein
View all literature mentionsYAP (D8H1X) XP Rabbit mAb (antibody)
RRID:AB_2650491
This recombinant monoclonal targets YAP
View all literature mentionsPhospho-MOB1 (Thr35) (D2F10) Rabbit mAb (antibody)
RRID:AB_11139998
This monoclonal targets Phospho-MOB1 (Thr35) (D2F10) Rabbit mAb
View all literature mentionsSAV1 (D6M6X) Rabbit mAb (antibody)
RRID:AB_2798176
This monoclonal targets SAV1
View all literature mentionsAnti-Mst1, phospho (Thr183) / Mst2, phospho (Thr180) Antibody, Unconjugated (antibody)
RRID:AB_330269
This unknown targets Mst1, phospho (Thr183) / Mst2, phospho (Thr180)
View all literature mentionsMerlin (D3S3W) Rabbit mAb #12888 (antibody)
RRID:AB_2650551
This monoclonal targets Merlin
View all literature mentionsPhospho-LATS1 (Thr1079) (D57D3) Rabbit mAb (antibody)
RRID:AB_10971635
This monoclonal targets Phospho-LATS1 (Thr1079) (D57D3) Rabbit mAb
View all literature mentionsAnti-LATS2 (D83D6) Rabbit mAb (antibody)
RRID:AB_10835233
This monoclonal targets LATS2 (D83D6)
View all literature mentionsLATS1 (C66B5) Rabbit mAb (antibody)
RRID:AB_2133513
This monoclonal targets LATS1
View all literature mentionsHA-Tag (C29F4) Rabbit mAb (HRP Conjugate) (antibody)
RRID:AB_2798368
This monoclonal targets
View all literature mentionsVinculin (E1E9V) XP® (antibody)
RRID:AB_2728768
This monoclonal targets Vinculin
View all literature mentionsCyr61 (H-78) (antibody)
RRID:AB_2088733
This polyclonal targets Cyr61 (H-78)
View all literature mentionsGoat Anti-Rat IgG (H+L) Antibody, Alexa Fluor ?? 647 Conjugated (antibody)
RRID:AB_141778
This polyclonal secondary targets IgG (H+L)
View all literature mentionsGoat anti-Rabbit IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 555 (antibody)
RRID:AB_2535849
This polyclonal secondary targets IgG (H+L)
View all literature mentionsPeroxidase IgG Fraction Monoclonal Mouse Anti-Rabbit IgG, light chain specific (antibody)
RRID:AB_2339149
This monoclonal secondary targets IgG, Light Chain Specific
View all literature mentionsPeroxidase-AffiniPure Goat Anti-Rabbit IgG (H+L) (antibody)
RRID:AB_2313567
This polyclonal targets IgG (H+L)
View all literature mentionsPeroxidase-AffiniPure Goat Anti-Mouse IgG (H + L) (antibody)
RRID:AB_10015289
This polyclonal targets IgG (H + L)
View all literature mentionsKeratin, type I; cytokeratin 19 antibody - Kemler, R.; MPI fuer Immunobiologie (antibody)
RRID:AB_2133570
This monoclonal targets Keratin, type I; cytokeratin 19
View all literature mentionsLATS1/LATS2 Antibody (antibody)
RRID:AB_2133375
This unknown targets LATS1/LATS2
View all literature mentionsKi67 antibody - Proliferation Marker (antibody)
RRID:AB_443209
This polyclonal targets Ki67 antibody - Proliferation Marker
View all literature mentionsCytokeratin 19 antibody [EP1580Y] (antibody)
RRID:AB_2281020
This monoclonal targets Human Cytokeratin 19
View all literature mentionsWWC2 antibody (antibody)
RRID:AB_11140331
This polyclonal targets WWC2 antibody
View all literature mentionsSTK3 antibody [EP1466Y] (antibody)
RRID:AB_882734
This monoclonal targets STK3
View all literature mentionsMouse Anti-MST1 Monoclonal Antibody, Unconjugated, Clone 7 (antibody)
RRID:AB_398365
This monoclonal targets MST1
View all literature mentionsMouse Anti-Hsp90 Monoclonal Antibody, Unconjugated, Clone 68 (antibody)
RRID:AB_397798
This monoclonal targets Hsp90
View all literature mentionsAnti-WWTR1 antibody produced in rabbit (antibody)
RRID:AB_1080602
This unknown targets Human WWTR1
View all literature mentionsMouse Anti-FLAG?? Monoclonal Antibody, Horseradish Peroxidase Conjugated (antibody)
RRID:AB_439702
This monoclonal targets FLAG
View all literature mentionsMonoclonal Anti-alpha-Tubulin antibody produced in mouse (antibody)
RRID:AB_477583
This monoclonal targets alpha-Tubulin
View all literature mentionsHNF4α (C11F12) Rabbit mAb (antibody)
RRID:AB_2295208
This monoclonal targets HNF4alpha
View all literature mentionsSox9 (D8G8H) Rabbit mAb #82630 (antibody)
RRID:AB_2665492
This monoclonal targets Sox9
View all literature mentionsRecombinant Anti-Striatin 4 antibody [EPR11801] (antibody)
RRID:AB_2927671
This monoclonal targets Striatin 4
View all literature mentionsAnti-FAM40B antibody produced in rabbit (antibody)
RRID:AB_1848399
This polyclonal targets FAM40B antibody produced in rabbit
View all literature mentionsHGK (D19H10) Rabbit mAb (antibody)
RRID:AB_10694775
This monoclonal targets HGK (D19H10) Rabbit mAb
View all literature mentionsPhospho-YAP (Ser127) Antibody (antibody)
RRID:AB_2218913
This polyclonal targets YAP1
View all literature mentionsYAP/TAZ (D24E4) Rabbit mAb (antibody)
RRID:AB_10950494
This monoclonal targets Monoclonal antibody is produced by immunizing animals with a synthetic peptide corresponding to residues surrounding Asp362 of human TAZ protein
View all literature mentionsYAP (D8H1X) XP Rabbit mAb (antibody)
RRID:AB_2650491
This recombinant monoclonal targets YAP
View all literature mentionsPhospho-MOB1 (Thr35) (D2F10) Rabbit mAb (antibody)
RRID:AB_11139998
This monoclonal targets Phospho-MOB1 (Thr35) (D2F10) Rabbit mAb
View all literature mentionsSAV1 (D6M6X) Rabbit mAb (antibody)
RRID:AB_2798176
This monoclonal targets SAV1
View all literature mentionsAnti-Mst1, phospho (Thr183) / Mst2, phospho (Thr180) Antibody, Unconjugated (antibody)
RRID:AB_330269
This unknown targets Mst1, phospho (Thr183) / Mst2, phospho (Thr180)
View all literature mentionsMerlin (D3S3W) Rabbit mAb #12888 (antibody)
RRID:AB_2650551
This monoclonal targets Merlin
View all literature mentionsPhospho-LATS1 (Thr1079) (D57D3) Rabbit mAb (antibody)
RRID:AB_10971635
This monoclonal targets Phospho-LATS1 (Thr1079) (D57D3) Rabbit mAb
View all literature mentionsAnti-LATS2 (D83D6) Rabbit mAb (antibody)
RRID:AB_10835233
This monoclonal targets LATS2 (D83D6)
View all literature mentionsLATS1 (C66B5) Rabbit mAb (antibody)
RRID:AB_2133513
This monoclonal targets LATS1
View all literature mentionsHA-Tag (C29F4) Rabbit mAb (HRP Conjugate) (antibody)
RRID:AB_2798368
This monoclonal targets
View all literature mentionsVinculin (E1E9V) XP® (antibody)
RRID:AB_2728768
This monoclonal targets Vinculin
View all literature mentionsCyr61 (H-78) (antibody)
RRID:AB_2088733
This polyclonal targets Cyr61 (H-78)
View all literature mentions
