Integrin-associated Lyn kinase promotes cell survival by suppressing acid sphingomyelinase activity

Daria A. Chudakova, Youssef Zeidan, Brian W. Wheeler, Jin Yu, Sergei A. Novgorodov, Mark S. Kindy, Yusuf A. Hannun, Tatyana I. Gudz

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Integrins govern cellular adhesion and transmit signals leading to activation of intracellular signaling pathways aimed to prevent apoptosis. Herein we report that attachment of oligodendrocytes (OLs) to fibronectin via αvβ3 integrin receptors rendered the cells more resistant to apoptosis than the cells attached to laminin via α6β1 integrins. Investigation of molecular mechanisms involved in αvβ3 integrin-mediated cell survival revealed that ligation of the integrin with fibronectin results in higher expression of activated Lyn kinase. Both in OLs and in the mouse brain, Lyn selectively associates with αvβ3 integrin, not with αvβ5 integrin, leading to suppression of acid sphingomyelinase activity and preventing ceramide-mediated apoptosis. In OLs, knockdown of Lyn with small interfering RNA resulted in OL apoptosis with concomitant accumulation of C16-ceramide due to activation of acid sphingomyelinase (ASMase) and sphingomyelin hydrolysis. Knocking down ASMase partially protected OLs from apoptosis. In the brain, ischemia/reperfusion (IR) triggered rearrangements in the αvβ3 integrin-Lyn kinase complex leading to disruption of Lyn kinase-mediated suppression of ASMase activity. Thus, co-immunoprecipitation studies revealed an increased association of αvβ3 integrin-Lyn kinase complex with ionotropic glutamate receptor subunits, GluR2 and GluR4, after cerebral IR. Sphingolipid analysis of the brain demonstrated significant accumulation of ceramide and sphingomyelin hydrolysis. The data suggest a novel mechanism for regulation of ASMase activity during cell adhesion in which Lyn acts as a key upstream kinase that may play a critical role in cerebral IR injury.

Original languageEnglish (US)
Pages (from-to)28806-28816
Number of pages11
JournalJournal of Biological Chemistry
Volume283
Issue number43
DOIs
StatePublished - Oct 24 2008
Externally publishedYes

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Sphingomyelin Phosphodiesterase
Integrins
Cell Survival
Phosphotransferases
Cells
Oligodendroglia
Acids
Apoptosis
Brain
Sphingomyelins
Ceramides
Brain Ischemia
Fibronectins
Reperfusion
Hydrolysis
Chemical activation
Ionotropic Glutamate Receptors
Sphingolipids
Cell adhesion
Laminin

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Chudakova, D. A., Zeidan, Y., Wheeler, B. W., Yu, J., Novgorodov, S. A., Kindy, M. S., ... Gudz, T. I. (2008). Integrin-associated Lyn kinase promotes cell survival by suppressing acid sphingomyelinase activity. Journal of Biological Chemistry, 283(43), 28806-28816. https://doi.org/10.1074/jbc.M803301200

Integrin-associated Lyn kinase promotes cell survival by suppressing acid sphingomyelinase activity. / Chudakova, Daria A.; Zeidan, Youssef; Wheeler, Brian W.; Yu, Jin; Novgorodov, Sergei A.; Kindy, Mark S.; Hannun, Yusuf A.; Gudz, Tatyana I.

In: Journal of Biological Chemistry, Vol. 283, No. 43, 24.10.2008, p. 28806-28816.

Research output: Contribution to journalArticle

Chudakova, DA, Zeidan, Y, Wheeler, BW, Yu, J, Novgorodov, SA, Kindy, MS, Hannun, YA & Gudz, TI 2008, 'Integrin-associated Lyn kinase promotes cell survival by suppressing acid sphingomyelinase activity', Journal of Biological Chemistry, vol. 283, no. 43, pp. 28806-28816. https://doi.org/10.1074/jbc.M803301200
Chudakova, Daria A. ; Zeidan, Youssef ; Wheeler, Brian W. ; Yu, Jin ; Novgorodov, Sergei A. ; Kindy, Mark S. ; Hannun, Yusuf A. ; Gudz, Tatyana I. / Integrin-associated Lyn kinase promotes cell survival by suppressing acid sphingomyelinase activity. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 43. pp. 28806-28816.
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