The Kelch Proteins Gpb1 and Gpb2 Inhibit Ras Activity via Association With the Yeast RasGAP Neurofibromin Homologs Ira1 and Ira2

Mol Cell. 2006 Jun 23;22(6):819-30. doi: 10.1016/j.molcel.2006.05.011.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • Adaptor Proteins, Signal Transducing
  • GPB1 protein, S cerevisiae
  • GTPase-Activating Proteins
  • Gpb2 protein, S cerevisiae
  • IRA1 protein, S cerevisiae
  • Neurofibromin 1
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • Protein-Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • RAS2 protein, S cerevisiae
  • ras Proteins
  • Adenylyl Cyclases