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The Kelch proteins Gpb1 and Gpb2 inhibit Ras activitv via association with the yeast RasGAP neurofibromin hornologs Ira1 and Ira2

Academic Article
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Overview

authors

  • Harashima, T.
  • Anderson, S.
  • Yates III, John
  • Heitman, J.

publication date

  • June 2006

journal

  • Molecular Cell  Journal

abstract

  • The G protein-coupled receptor Gpr1 and associated Galpha subunit Gpa2 govern dimorphic transitions in response to extracellular nutrients by signaling coordinately with Ras to activate adenylyl cyclase in the yeast Saccharomyces cerevisiae. Gpa2 forms a protein complex with the kelch Gbeta mimic subunits Gpb1/2, and previous studies demonstrate that Gpb1/2 negatively control cAMP-PKA signaling via Gpa2 and an unknown second target. Here, we define these targets of Gpb1/2 as the yeast neurofibromin homologs Ira1 and Ira2, which function as GTPase activating proteins of Ras. Gpb1/2 bind to a conserved C-terminal domain of Ira1/2, and loss of Gpb1/2 results in a destabilization of Ira1 and Ira2, leading to elevated levels of Ras2-GTP and unbridled cAMP-PKA signaling. Because the Gpb1/2 binding domain on Ira1/2 is conserved in the human neurofibromin protein, an analogous signaling network may contribute to the neoplastic development of neurofibromatosis type 1.

subject areas

  • Adaptor Proteins, Signal Transducing
  • Adenylyl Cyclases
  • Cell Transformation, Neoplastic
  • Cyclic AMP-Dependent Protein Kinases
  • GTPase-Activating Proteins
  • Gene Deletion
  • Humans
  • Neurofibromatosis 1
  • Neurofibromin 1
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • Repressor Proteins
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • ras Proteins
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Identity

International Standard Serial Number (ISSN)

  • 1097-2765

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2006.05.011

PubMed ID

  • 16793550
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Additional Document Info

start page

  • 819

end page

  • 830

volume

  • 22

issue

  • 6

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