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  Mutations in the Paxillin-binding Site of Integrin-linked Kinase (ILK) Destabilize the Pseudokinase Domain and Cause Embryonic Lethality in Mice

Moik, D., Böttcher, A., Makhina, T., Grashoff, C., Bulus, N., Zent, R., et al. (2013). Mutations in the Paxillin-binding Site of Integrin-linked Kinase (ILK) Destabilize the Pseudokinase Domain and Cause Embryonic Lethality in Mice. JOURNAL OF BIOLOGICAL CHEMISTRY, 288(26), 18863-18871. doi:10.1074/jbc.M113.470476.

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 Creators:
Moik, Daniel1, Author           
Böttcher, Anika1, Author           
Makhina, Tatiana1, Author           
Grashoff, Carsten2, Author           
Bulus, Nada3, Author
Zent, Roy3, Author
Fässler, Reinhard1, Author           
Affiliations:
1Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565147              
2Grashoff, Carsten / Molecular Mechanotransduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565150              
3external, ou_persistent22              

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Free keywords: FOCAL ADHESION KINASE; ALPHA-PARVIN; MOLECULAR DISSECTION; STRUCTURAL BASIS; ADAPTER PROTEIN; IN-VITRO; VASCULOGENESIS; LOCALIZATION; COMPLEX; PINCH
 Abstract: Integrin-linked kinase (ILK) localizes to focal adhesions (FAs) where it regulates cell spreading, migration, and growth factor receptor signaling. Previous reports showed that overexpressed ILK in which Val(386) and Thr(387) were substituted with glycine residues (ILK-VT/GG) could neither interact with paxillin nor localize to FA in cells expressing endogenous wild-type ILK, implying that paxillin binding to ILK is required for its localization to FAs. Here, we show that introducing this mutation into the germ line of mice (ILK-VT/GG) caused vasculogenesis defects, resulting in a general developmental delay and death at around embryonic day 12.5. Fibroblasts isolated from ILK-VT/GG mice contained mutant ILK in FAs, showed normal adhesion to and spreading on extracellular matrix substrates but displayed impaired migration. Biochemical analysis revealed that VT/GG substitutions decreased ILK protein stability leading to decreased ILK levels and reduced binding to paxillin and alpha-parvin. Because paxillin depletion did not affect ILK localization to FAs, the embryonic lethality and the in vitro migration defects are likely due to the reduced levels of ILK-VT/GG and diminished binding to parvins.

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Language(s): eng - English
 Dates: 2013
 Publication Status: Published in print
 Pages: 9
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000321335800024
DOI: 10.1074/jbc.M113.470476
 Degree: -

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Title: JOURNAL OF BIOLOGICAL CHEMISTRY
Source Genre: Journal
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Publ. Info: 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA : AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Pages: - Volume / Issue: 288 (26) Sequence Number: - Start / End Page: 18863 - 18871 Identifier: ISSN: 0021-9258