Scaffold proteins are multidomain proteins without enzymatic function that play a central role in coordinating signaling processes. The scaffold protein CNK1 interacts with pathway-specific signaling proteins and thereby regulates these respective pathways. Here, we revealed tyrosine phosphorylation as a critical regulation mechanism to control the function of CNK1. We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. Contrary, mutants preventing tyrosine phosphorylation promote matrix metalloproteinase MMP14 promoter activity. CNK1-driven cell proliferation partially depends on its tyrosine phosphorylation. Upon PDGF stimulation, CNK1 is recruited to the plasma membrane mediated by SRC. Knock down of CNK1 prevents PDGF-induced SRE-dependent gene expression, MMP14 promoter activity and cell proliferation. Thus, tyrosine phosphorylation is an important mechanism to control the subcellular localization of CNK1 and its distinct biological functions.
%0 Journal Article
%1 fischerDifferentialTyrosinePhosphorylation2015
%A Fischer, Adrian
%A Brummer, Tilman
%A Warscheid, Bettina
%A Radziwill, Gerald
%C Netherlands
%D 2015
%J Biochimica et biophysica acta
%K 14/*biosynthesis/genetics,Mutation,Phosphorylation/physiology,Platelet-derived Cell Cells,HeLa Cells,Humans,Intracellular Enzymologic/*physiology,Gene Expression Genetic/*physiology,Protein Kinases/genetics/*metabolism,to_read,Tyrosine Knockdown Membrane/enzymology/genetics,CNK1,Gene Metalloproteinase Peptides Proteins/genetics/*metabolism,Matrix Regions Regulation Signaling Techniques,HEK293 Transport/physiology,Scaffold and factor,Promoter growth phosphorylation,Tyrosine/genetics/metabolism protein,Signal transduction,SRC,src-Family
%N 11 Pt A
%P 2847--2855
%R 10.1016/j.bbamcr.2015.08.014
%T Differential Tyrosine Phosphorylation Controls the Function of CNK1 as a Molecular Switch in Signal Transduction.
%V 1853
%X Scaffold proteins are multidomain proteins without enzymatic function that play a central role in coordinating signaling processes. The scaffold protein CNK1 interacts with pathway-specific signaling proteins and thereby regulates these respective pathways. Here, we revealed tyrosine phosphorylation as a critical regulation mechanism to control the function of CNK1. We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. Contrary, mutants preventing tyrosine phosphorylation promote matrix metalloproteinase MMP14 promoter activity. CNK1-driven cell proliferation partially depends on its tyrosine phosphorylation. Upon PDGF stimulation, CNK1 is recruited to the plasma membrane mediated by SRC. Knock down of CNK1 prevents PDGF-induced SRE-dependent gene expression, MMP14 promoter activity and cell proliferation. Thus, tyrosine phosphorylation is an important mechanism to control the subcellular localization of CNK1 and its distinct biological functions.
@article{fischerDifferentialTyrosinePhosphorylation2015,
abstract = {Scaffold proteins are multidomain proteins without enzymatic function that play a central role in coordinating signaling processes. The scaffold protein CNK1 interacts with pathway-specific signaling proteins and thereby regulates these respective pathways. Here, we revealed tyrosine phosphorylation as a critical regulation mechanism to control the function of CNK1. We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. Contrary, mutants preventing tyrosine phosphorylation promote matrix metalloproteinase MMP14 promoter activity. CNK1-driven cell proliferation partially depends on its tyrosine phosphorylation. Upon PDGF stimulation, CNK1 is recruited to the plasma membrane mediated by SRC. Knock down of CNK1 prevents PDGF-induced SRE-dependent gene expression, MMP14 promoter activity and cell proliferation. Thus, tyrosine phosphorylation is an important mechanism to control the subcellular localization of CNK1 and its distinct biological functions.},
added-at = {2024-05-17T13:01:35.000+0200},
address = {Netherlands},
author = {Fischer, Adrian and Brummer, Tilman and Warscheid, Bettina and Radziwill, Gerald},
biburl = {https://www.bibsonomy.org/bibtex/29c6b020e1558f4c3e8dc7765ec99bd39/warscheidlab},
copyright = {Copyright {\copyright} 2015 Elsevier B.V. All rights reserved.},
doi = {10.1016/j.bbamcr.2015.08.014},
interhash = {aabbe535ac27f05985738cd94c7a2954},
intrahash = {9c6b020e1558f4c3e8dc7765ec99bd39},
issn = {0006-3002},
journal = {Biochimica et biophysica acta},
keywords = {14/*biosynthesis/genetics,Mutation,Phosphorylation/physiology,Platelet-derived Cell Cells,HeLa Cells,Humans,Intracellular Enzymologic/*physiology,Gene Expression Genetic/*physiology,Protein Kinases/genetics/*metabolism,to_read,Tyrosine Knockdown Membrane/enzymology/genetics,CNK1,Gene Metalloproteinase Peptides Proteins/genetics/*metabolism,Matrix Regions Regulation Signaling Techniques,HEK293 Transport/physiology,Scaffold and factor,Promoter growth phosphorylation,Tyrosine/genetics/metabolism protein,Signal transduction,SRC,src-Family},
langid = {english},
month = nov,
number = {11 Pt A},
pages = {2847--2855},
pmid = {26319181},
timestamp = {2024-05-17T13:01:35.000+0200},
title = {Differential Tyrosine Phosphorylation Controls the Function of {{CNK1}} as a Molecular Switch in Signal Transduction.},
volume = 1853,
year = 2015
}