Format

Send to

Choose Destination
Biochemistry. 2017 Sep 5;56(35):4722-4731. doi: 10.1021/acs.biochem.7b00616. Epub 2017 Aug 23.

Regulation of Focal Adhesion Kinase through a Direct Interaction with an Endogenous Inhibitor.

Author information

1
Department of Cell and Molecular Physiology and ‡Department of Medicine, Cardiovascular Research Institute, Stritch School of Medicine, Loyola University Chicago , Maywood, Illinois 60153, United States.

Abstract

Focal adhesion kinase (FAK) plays a key role in integrin and growth factor signaling pathways. FAK-related non-kinase (FRNK) is an endogenous inhibitor of FAK that shares its primary structure with the C-terminal third of FAK. FAK S910 phosphorylation is known to regulate FAK protein-protein interactions, but the role of the equivalent site on FRNK (S217) is unknown. Here we determined that S217 is highly phosphorylated by ERK in cultured rat aortic smooth muscle cells. Blocking phosphorylation by mutation (S217A) greatly increased FRNK inhibitory potency, resulting in strong inhibition of FAK autophosphorylation at Y397 and induction of smooth muscle cell apoptosis. FRNK has been proposed to compete for FAK anchoring sites in focal adhesions, but we did not detect displacement of FAK by WT-FRNK or superinhibitory S217A-FRNK. Instead, we found FRNK interacted directly with FAK, and this interaction is markedly strengthened for the superinhibitory S217A-FRNK. The results suggest that FRNK limits growth and survival signaling pathways by binding directly to FAK in an inhibitory complex, and this inhibition is relieved by phosphorylation of FRNK at S217.

PMID:
28782937
DOI:
10.1021/acs.biochem.7b00616
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center