Novel Gbeta Mimic Kelch Proteins (Gpb1 and Gpb2 Connect G-Protein Signaling to Ras via Yeast Neurofibromin Homologs Ira1 and Ira2. A Model for Human NF1
Abstract
The Neurofibromatosis type 1 (NF1) gene encodes a large tumor suppressor protein neurofibromin which is a Ras GTPase-activating protein (RasGAP) activity. Although the NF1 gene was identified over a decade ago the biological roles of neurofibromin in cellular processes remain unclear. Therefore it is crucial for therapy and developing new drugs for NF1 patients to elucidate how the RasGAP activity of neurofibromin is controlled. To achieve this goal it is also important to identify regulatory elements for neurofibromin. We are investigating the molecular mechanisms by which the Ras GAP activity of the yeast neurofibromin homologs Ira1/2 is regulated as a model to understand human NFI. We have found that the kelch Gb subunit mimics Gpb1/2 interact with Ira1/2 and control the Ras GAP activity of Ira1/2. Hem we found that the Gpb1/2 proteins are localized to the cell membrane in a Gpa2 dependent manner and function at the cell membrane. Gpb1/2 bind to the C-terminus of Ira1/2 and stabilize the Ira1/2 proteins. Moreover we also identified a Gpb1/2 binding domain near the C-terminus of Ira1/2 (GBD) that is significantly conserved in neurofibromin homologs including a human counterpart. Therefore, similar regulatory mechanisms might be conserved in evolution.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2007
- Accession Number
- ADA479389
Entities
People
- Joseph Heitman
- Toshiaki Harashima
Organizations
- Duke University