The integrity of cholesterol-enriched microdomains is essential for the constitutive high activity of protein kinase B in tumour cells

S. Elhyany, E. Assa-Kunik, S. Tsory, T. Muller, S. Fedida, S. Segal, D. Fishman

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

A deregulated activity of PKB/Akt (where PKB stands for protein kinase B) renders tumour cells resistant to a variety of apoptosis-inducing stimuli. Elucidation of the mechanisms responsible for this deregulation is of prime importance for the development of novel anti-cancer drugs. Results of the present study demonstrate that the constitutive activity of PKB/Akt in B16BL6 melanoma cells depends on the integrity of cholesterol-enriched membrane microdomains, since the exposure of cells to cholesterol-depleting agents decreases the phosphorylation of this enzyme, with no change in its total protein level. Inhibitors of Hsp90 (heat-shock protein 90) decreased phosphorylation of PKB/Akt with a similar pattern. Dephosphorylation of the enzyme, as a consequence of raft disintegration, could be precluded by inhibition of serine/threonine (but not tyrosine) phosphatases. Our results imply that destabilization of lipid rafts seemingly affects the association of Hsp90 with the respective serine/threonine phosphatases, thereby increasing the accessibility to PKB/Akt to deactivating phosphatases. We have found recently that reconstituted expression of H-2K class I glycoproteins in class I-deficient B16BL6 cells also decreases the phosphorylation of PKB/Akt. Therefore it is possible that raft-associated regulation of this important enzyme involves both H-2K glycoproteins and Hsp90.

Original languageEnglish
Pages (from-to)837-839
Number of pages3
JournalBiochemical Society Transactions
Volume32
Issue number5
DOIs
StatePublished - 1 Nov 2004

Keywords

  • Cholesterol-enriched microdomain
  • Lipid raft
  • Major histocompalibilily complex (MHC)
  • Protein kinase B

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