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Regulation of proto-oncogenic dbl by chaperone-controlled, ubiquitin-mediated degradation.

The dbl proto-oncogene product is a prototype of a growing family of guanine nucleotide exchange factors (GEFs) that stimulate the activation of small GTP-binding proteins from the Rho family. Mutations that result in the loss of proto-Dbl's amino terminus produce a variant with constitutive GEF activity and high oncogenic potential. Here, we show that proto-Dbl is a short-lived protein that is kept at low levels in cells by efficient ubiquitination and degradation. The cellular fate of proto-Dbl is regulated by interactions with the chaperones Hsc70 and Hsp90 and the protein-ubiquitin ligase CHIP, and these interactions are mediated by the spectrin domain of proto-Dbl. We show that CHIP is the E3 ligase responsible for ubiquitination and proteasomal degradation of proto-Dbl, while Hsp90 functions to stabilize the protein. Onco-Dbl, lacking the spectrin homology domain, cannot bind these regulators and therefore accumulates in cells at high levels, leading to persistent stimulation of its downstream signaling pathways.

Pubmed ID: 17178836

Authors

  • Kamynina E
  • Kauppinen K
  • Duan F
  • Muakkassa N
  • Manor D

Journal

Molecular and cellular biology

Publication Data

March 14, 2007

Associated Grants

  • Agency: NCI NIH HHS, Id: CA82391
  • Agency: NIDDK NIH HHS, Id: T32DK-007158-30

Mesh Terms

  • Animals
  • COS Cells
  • Cercopithecus aethiops
  • Guanine Nucleotide Exchange Factors
  • HSC70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Mice
  • Models, Biological
  • Molecular Chaperones
  • Mutation
  • NIH 3T3 Cells
  • Proteasome Endopeptidase Complex
  • Protein Structure, Tertiary
  • Retroviridae Proteins, Oncogenic
  • Spectrin
  • Spodoptera
  • Transfection
  • Ubiquitin-Protein Ligases