Negative regulation of PI 3-kinase by Ruk, a novel adaptor protein

I Gout, G Middleton, J Adu, N N Ninkina, L B Drobot, V Filonenko, G Matsuka, A M Davies, M Waterfield, V L Buchman

Research output: Contribution to journalArticlepeer-review

122 Citations (Scopus)

Abstract

Class I-A phosphatidylinositol 3-kinase (PI3-kinase) is a key component of important intracellular signalling cascades. We have identified an adaptor protein, Ruk(1), which forms complexes with the PI 3-kinase holoenzyme in vitro and in vivo. This interaction involves the proline-rich region of Ruk and the SH3 domain of the p85 alpha regulatory subunit of the class I-A PI 3-kinase. In contrast to many other adaptor proteins that activate PI 3-kinase, interaction with Ruk(1) substantially inhibits the lipid kinase activity of the enzyme. Overexpression of Ruk(1) in cultured primary neurons induces apoptosis, an effect that could be reversed by co-expression of constitutively activated forms of the p110 alpha a catalytic subunit of PI 3-kinase or its downstream effector PKB/Akt, Our data provide evidence for the existence of a negative regulator of the PI 3-kinase signalling pathway that is essential for maintaining cellular homeostasis. Structural similarities between Ruk, CIN85 and CD2AP/CMS suggest that these proteins form a novel family of adaptor molecules that are involved in various intracellular signalling pathways.

Original languageEnglish
Pages (from-to)4015-4025
Number of pages11
JournalEMBO Journal
Volume19
Publication statusPublished - 1 Aug 2000

Keywords

  • adaptor protein
  • neuronal apoptosis
  • phosphoinositide 3-kinase
  • signal transduction
  • NERVE GROWTH-FACTOR
  • PLECKSTRIN HOMOLOGY DOMAINS
  • PHOSPHOINOSITIDE 3-OH KINASE
  • PHOSPHATIDYLINOSITOL 3-KINASE
  • TUMOR-SUPPRESSOR
  • TYROSINE KINASE
  • SENSORY NEURONS
  • P85 SUBUNIT
  • SIGNAL-TRANSDUCTION
  • CELL-SURVIVAL

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