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Title: Non-catalytic signaling by pseudokinase ILK for regulating cell adhesion

Abstract

Dynamic communication between integrin-containing complexes (focal adhesions, FAs) and actin filaments is critical for regulating cell adhesion. Pseudokinase ILK plays a key role in this process but the underlying mechanism remains highly elusive. Here in this paper we show that by recruiting FA adaptors PINCH and Parvin into a heterotrimeric complex (IPP), ILK triggers F-actin filament bundling – a process known to generate force/mechanical signal to promote cytoskeleton reassembly and dynamic cell adhesion. Structural, biochemical, and functional analyses revealed that the F-actin bundling is orchestrated by two previously unrecognized WASP-Homology-2 actin binding motifs within IPP, one from PINCH and the other from Parvin. Strikingly, this process is also sensitized to Mg-ATP bound to the pseudoactive site of ILK and its dysregulation severely impairs stress fibers formation, cell spreading, and migration. These data identify a crucial mechanism for ILK, highlighting its uniqueness as a pseudokinase to transduce non-catalytic signal and regulate cell adhesion.

Authors:
 [1];  [1];  [2];  [1];  [3];  [1];  [2]
  1. Cleveland Clinic, Cleveland, OH (United States)
  2. Cleveland Clinic, Cleveland, OH (United States); Case Western Reserve Univ., Cleveland, OH (United States)
  3. Case Western Reserve Univ., Cleveland, OH (United States)
Publication Date:
Research Org.:
Cleveland Clinic, Cleveland, OH (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1483387
Grant/Contract Number:  
AC02-06CH11357; HL058758; 1S10RR026820-01
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Vaynberg, Julia, Fukuda, Koichi, Lu, Fan, Bialkowska, Katarzyna, Chen, Yinghua, Plow, Edward F., and Qin, Jun. Non-catalytic signaling by pseudokinase ILK for regulating cell adhesion. United States: N. p., 2018. Web. doi:10.1038/s41467-018-06906-7.
Vaynberg, Julia, Fukuda, Koichi, Lu, Fan, Bialkowska, Katarzyna, Chen, Yinghua, Plow, Edward F., & Qin, Jun. Non-catalytic signaling by pseudokinase ILK for regulating cell adhesion. United States. doi:10.1038/s41467-018-06906-7.
Vaynberg, Julia, Fukuda, Koichi, Lu, Fan, Bialkowska, Katarzyna, Chen, Yinghua, Plow, Edward F., and Qin, Jun. Fri . "Non-catalytic signaling by pseudokinase ILK for regulating cell adhesion". United States. doi:10.1038/s41467-018-06906-7. https://www.osti.gov/servlets/purl/1483387.
@article{osti_1483387,
title = {Non-catalytic signaling by pseudokinase ILK for regulating cell adhesion},
author = {Vaynberg, Julia and Fukuda, Koichi and Lu, Fan and Bialkowska, Katarzyna and Chen, Yinghua and Plow, Edward F. and Qin, Jun},
abstractNote = {Dynamic communication between integrin-containing complexes (focal adhesions, FAs) and actin filaments is critical for regulating cell adhesion. Pseudokinase ILK plays a key role in this process but the underlying mechanism remains highly elusive. Here in this paper we show that by recruiting FA adaptors PINCH and Parvin into a heterotrimeric complex (IPP), ILK triggers F-actin filament bundling – a process known to generate force/mechanical signal to promote cytoskeleton reassembly and dynamic cell adhesion. Structural, biochemical, and functional analyses revealed that the F-actin bundling is orchestrated by two previously unrecognized WASP-Homology-2 actin binding motifs within IPP, one from PINCH and the other from Parvin. Strikingly, this process is also sensitized to Mg-ATP bound to the pseudoactive site of ILK and its dysregulation severely impairs stress fibers formation, cell spreading, and migration. These data identify a crucial mechanism for ILK, highlighting its uniqueness as a pseudokinase to transduce non-catalytic signal and regulate cell adhesion.},
doi = {10.1038/s41467-018-06906-7},
journal = {Nature Communications},
issn = {2041-1723},
number = 1,
volume = 9,
place = {United States},
year = {2018},
month = {10}
}

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Cited by: 13 works
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