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Mutual dependence of the MRTF-SRF and YAP-TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics.

Abstract Both the MRTF-SRF and the YAP-TEAD transcriptional regulatory networks respond to extracellular signals and mechanical stimuli. We show that the MRTF-SRF pathway is activated in cancer-associated fibroblasts (CAFs). The MRTFs are required in addition to the YAP pathway for CAF contractile and proinvasive properties. We compared MRTF-SRF and YAP-TEAD target gene sets and identified genes directly regulated by one pathway, the other, or both. Nevertheless, the two pathways exhibit mutual dependence. In CAFs, expression of direct MRTF-SRF genomic targets is also dependent on YAP-TEAD activity, and, conversely, YAP-TEAD target gene expression is also dependent on MRTF-SRF signaling. In normal fibroblasts, expression of activated MRTF derivatives activates YAP, while activated YAP derivatives activate MRTF. Cross-talk between the pathways requires recruitment of MRTF and YAP to DNA via their respective DNA-binding partners (SRF and TEAD) and is therefore indirect, arising as a consequence of activation of their target genes. In both CAFs and normal fibroblasts, we found that YAP-TEAD activity is sensitive to MRTF-SRF-induced contractility, while MRTF-SRF signaling responds to YAP-TEAD-dependent TGFβ signaling. Thus, the MRF-SRF and YAP-TEAD pathways interact indirectly through their ability to control cytoskeletal dynamics.
PMID
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Authors

Mayor MeshTerms
Keywords

MRTF

SRF

TEAD

YAP

cancer-associated fibroblast

mechanotransduction

transcription

Journal Title genes & development
Publication Year Start




PMID- 29317486
OWN - NLM
STAT- In-Data-Review
LR  - 20180120
IS  - 1549-5477 (Electronic)
IS  - 0890-9369 (Linking)
VI  - 31
IP  - 23-24
DP  - 2017 Dec 1
TI  - Mutual dependence of the MRTF-SRF and YAP-TEAD pathways in cancer-associated
      fibroblasts is indirect and mediated by cytoskeletal dynamics.
PG  - 2361-2375
LID - 10.1101/gad.304501.117 [doi]
AB  - Both the MRTF-SRF and the YAP-TEAD transcriptional regulatory networks respond to
      extracellular signals and mechanical stimuli. We show that the MRTF-SRF pathway
      is activated in cancer-associated fibroblasts (CAFs). The MRTFs are required in
      addition to the YAP pathway for CAF contractile and proinvasive properties. We
      compared MRTF-SRF and YAP-TEAD target gene sets and identified genes directly
      regulated by one pathway, the other, or both. Nevertheless, the two pathways
      exhibit mutual dependence. In CAFs, expression of direct MRTF-SRF genomic targets
      is also dependent on YAP-TEAD activity, and, conversely, YAP-TEAD target gene
      expression is also dependent on MRTF-SRF signaling. In normal fibroblasts,
      expression of activated MRTF derivatives activates YAP, while activated YAP
      derivatives activate MRTF. Cross-talk between the pathways requires recruitment
      of MRTF and YAP to DNA via their respective DNA-binding partners (SRF and TEAD)
      and is therefore indirect, arising as a consequence of activation of their target
      genes. In both CAFs and normal fibroblasts, we found that YAP-TEAD activity is
      sensitive to MRTF-SRF-induced contractility, while MRTF-SRF signaling responds to
      YAP-TEAD-dependent TGFbeta signaling. Thus, the MRF-SRF and YAP-TEAD pathways
      interact indirectly through their ability to control cytoskeletal dynamics.
CI  - (c) 2018 Foster et al.; Published by Cold Spring Harbor Laboratory Press.
FAU - Foster, Charles T
AU  - Foster CT
AD  - Signalling and Transcription Group, Francis Crick Institute, London NW1 1AT,
      United Kingdom.
FAU - Gualdrini, Francesco
AU  - Gualdrini F
AD  - Signalling and Transcription Group, Francis Crick Institute, London NW1 1AT,
      United Kingdom.
FAU - Treisman, Richard
AU  - Treisman R
AUID- ORCID: http://orcid.org/0000-0002-9658-0067
AD  - Signalling and Transcription Group, Francis Crick Institute, London NW1 1AT,
      United Kingdom.
LA  - eng
PT  - Journal Article
DEP - 20180109
PL  - United States
TA  - Genes Dev
JT  - Genes & development
JID - 8711660
OTO - NOTNLM
OT  - MRTF
OT  - SRF
OT  - TEAD
OT  - YAP
OT  - cancer-associated fibroblast
OT  - mechanotransduction
OT  - transcription
EDAT- 2018/01/11 06:00
MHDA- 2018/01/11 06:00
CRDT- 2018/01/11 06:00
PHST- 2017/07/10 00:00 [received]
PHST- 2017/12/12 00:00 [accepted]
PHST- 2018/01/11 06:00 [pubmed]
PHST- 2018/01/11 06:00 [medline]
PHST- 2018/01/11 06:00 [entrez]
AID - gad.304501.117 [pii]
AID - 10.1101/gad.304501.117 [doi]
PST - ppublish
SO  - Genes Dev. 2017 Dec 1;31(23-24):2361-2375. doi: 10.1101/gad.304501.117. Epub 2018
      Jan 9.