10779/crick.12668828.v1
A Elbediwy
A
Elbediwy
ZI Vincent-Mistiaen
ZI
Vincent-Mistiaen
B Spencer-Dene
B
Spencer-Dene
RK Stone
RK
Stone
S Boeing
S
Boeing
SK Wculek
SK
Wculek
J Cordero
J
Cordero
EH Tan
EH
Tan
R Ridgway
R
Ridgway
VG Brunton
VG
Brunton
E Sahai
E
Sahai
H Gerhardt
H
Gerhardt
A Behrens
A
Behrens
I Malanchi
I
Malanchi
OJ Sansom
OJ
Sansom
BJ Thompson
BJ
Thompson
Integrin signalling regulates YAP and TAZ to control skin homeostasis
The Francis Crick Institute
2020
Hippo pathway
Integrin
Stratified squamous epithelium
TAZ
Yes-associated protein
Adaptor Proteins, Signal Transducing
Animals
Cell Cycle Proteins
Cell Differentiation
Cell Line
Cell Nucleus
Dasatinib
Epithelium
ErbB Receptors
Gene Expression Regulation
Homeostasis
Humans
Integrins
Intracellular Signaling Peptides and Proteins
Keratinocytes
Mice
Neoplasms, Squamous Cell
Phosphatidylinositol 3-Kinases
Phosphoproteins
Protein Stability
Protein Transport
Signal Transduction
Skin
Stem Cells
Transcription Factors
Wound Healing
src-Family Kinases
Thompson FC001180
Malanchi FC001112
Behrens FC001039
Sahai FC001144
HP
CB
06 Biological Sciences
11 Medical and Health Sciences
2020-07-17 16:38:54
Journal contribution
https://crick.figshare.com/articles/journal_contribution/Integrin_signalling_regulates_YAP_and_TAZ_to_control_skin_homeostasis/12668828
The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib.