FAK auto-phosphorylation site tyrosine 397 is required for development but dispensable for normal skin homeostasis.
Focal adhesion kinase (FAK) is an intensely studied non-receptor tyrosine kinase with roles in cancer and other common human diseases. Despite the large interest in FAK, the in vivo contribution of FAK auto-phosphorylation site tyrosine (Y) 397 to FAK function is incompletely understood. To study FA...
Main Authors: | , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2018-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC6042779?pdf=render |
id |
doaj-1109ccb00a0143719d68081d1a670d0e |
---|---|
record_format |
Article |
spelling |
doaj-1109ccb00a0143719d68081d1a670d0e2020-11-25T00:24:50ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01137e020055810.1371/journal.pone.0200558FAK auto-phosphorylation site tyrosine 397 is required for development but dispensable for normal skin homeostasis.Joel B HeimCera A McDonaldSaranya P WylesSindhuja Sominidi-DamodaranEdwin J SquirewellMing LiCatherine MotsonelidzeRalph T BöttcherJan van DeursenAlexander MevesFocal adhesion kinase (FAK) is an intensely studied non-receptor tyrosine kinase with roles in cancer and other common human diseases. Despite the large interest in FAK, the in vivo contribution of FAK auto-phosphorylation site tyrosine (Y) 397 to FAK function is incompletely understood. To study FAK Y397 in vivo we analyzed mice with 'non-phosphorylatable' Y-to-phenylalanine (F) and 'phospho-mimicking' Y-to-glutamate (E) mutations in the germline. We found that FAK Y397F mice die early during embryogenesis with abnormal angiogenesis like FAK kinase-dead mice. When Y397 is mutated to a glutamate mice survive beyond mid-gestation like mice where Y397 is lost by deletion of FAK exon 15. In culture, defects in proliferation, invasion and gene expression were more severe with the FAK Y397F than with the FAK Y397E mutation despite the inability of FAK Y397E to bind SRC. Conditional expression of FAK Y397F or Y397E in unchallenged avascular epidermis, however, resulted in no appreciable phenotype. We conclude that FAK Y397 is required for the highly dynamic tissue remodeling during development but dispensable for normal homeostasis of avascular epidermis. In contrast to the Y397F mutation, FAK Y397E retains sufficient biological activity to allow for development beyond mid-gestation.http://europepmc.org/articles/PMC6042779?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Joel B Heim Cera A McDonald Saranya P Wyles Sindhuja Sominidi-Damodaran Edwin J Squirewell Ming Li Catherine Motsonelidze Ralph T Böttcher Jan van Deursen Alexander Meves |
spellingShingle |
Joel B Heim Cera A McDonald Saranya P Wyles Sindhuja Sominidi-Damodaran Edwin J Squirewell Ming Li Catherine Motsonelidze Ralph T Böttcher Jan van Deursen Alexander Meves FAK auto-phosphorylation site tyrosine 397 is required for development but dispensable for normal skin homeostasis. PLoS ONE |
author_facet |
Joel B Heim Cera A McDonald Saranya P Wyles Sindhuja Sominidi-Damodaran Edwin J Squirewell Ming Li Catherine Motsonelidze Ralph T Böttcher Jan van Deursen Alexander Meves |
author_sort |
Joel B Heim |
title |
FAK auto-phosphorylation site tyrosine 397 is required for development but dispensable for normal skin homeostasis. |
title_short |
FAK auto-phosphorylation site tyrosine 397 is required for development but dispensable for normal skin homeostasis. |
title_full |
FAK auto-phosphorylation site tyrosine 397 is required for development but dispensable for normal skin homeostasis. |
title_fullStr |
FAK auto-phosphorylation site tyrosine 397 is required for development but dispensable for normal skin homeostasis. |
title_full_unstemmed |
FAK auto-phosphorylation site tyrosine 397 is required for development but dispensable for normal skin homeostasis. |
title_sort |
fak auto-phosphorylation site tyrosine 397 is required for development but dispensable for normal skin homeostasis. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2018-01-01 |
description |
Focal adhesion kinase (FAK) is an intensely studied non-receptor tyrosine kinase with roles in cancer and other common human diseases. Despite the large interest in FAK, the in vivo contribution of FAK auto-phosphorylation site tyrosine (Y) 397 to FAK function is incompletely understood. To study FAK Y397 in vivo we analyzed mice with 'non-phosphorylatable' Y-to-phenylalanine (F) and 'phospho-mimicking' Y-to-glutamate (E) mutations in the germline. We found that FAK Y397F mice die early during embryogenesis with abnormal angiogenesis like FAK kinase-dead mice. When Y397 is mutated to a glutamate mice survive beyond mid-gestation like mice where Y397 is lost by deletion of FAK exon 15. In culture, defects in proliferation, invasion and gene expression were more severe with the FAK Y397F than with the FAK Y397E mutation despite the inability of FAK Y397E to bind SRC. Conditional expression of FAK Y397F or Y397E in unchallenged avascular epidermis, however, resulted in no appreciable phenotype. We conclude that FAK Y397 is required for the highly dynamic tissue remodeling during development but dispensable for normal homeostasis of avascular epidermis. In contrast to the Y397F mutation, FAK Y397E retains sufficient biological activity to allow for development beyond mid-gestation. |
url |
http://europepmc.org/articles/PMC6042779?pdf=render |
work_keys_str_mv |
AT joelbheim fakautophosphorylationsitetyrosine397isrequiredfordevelopmentbutdispensablefornormalskinhomeostasis AT ceraamcdonald fakautophosphorylationsitetyrosine397isrequiredfordevelopmentbutdispensablefornormalskinhomeostasis AT saranyapwyles fakautophosphorylationsitetyrosine397isrequiredfordevelopmentbutdispensablefornormalskinhomeostasis AT sindhujasominididamodaran fakautophosphorylationsitetyrosine397isrequiredfordevelopmentbutdispensablefornormalskinhomeostasis AT edwinjsquirewell fakautophosphorylationsitetyrosine397isrequiredfordevelopmentbutdispensablefornormalskinhomeostasis AT mingli fakautophosphorylationsitetyrosine397isrequiredfordevelopmentbutdispensablefornormalskinhomeostasis AT catherinemotsonelidze fakautophosphorylationsitetyrosine397isrequiredfordevelopmentbutdispensablefornormalskinhomeostasis AT ralphtbottcher fakautophosphorylationsitetyrosine397isrequiredfordevelopmentbutdispensablefornormalskinhomeostasis AT janvandeursen fakautophosphorylationsitetyrosine397isrequiredfordevelopmentbutdispensablefornormalskinhomeostasis AT alexandermeves fakautophosphorylationsitetyrosine397isrequiredfordevelopmentbutdispensablefornormalskinhomeostasis |
_version_ |
1725351265000488960 |