Regulating Neurofibromin Through Degradation, Dimerization, and Binding to SPRED1
Abstract
We have previously shown that SPRED1 regulates localization of neurofibromin (the protein product of the NF1 gene) to the plasma membrane where it functions as a negative regulator of RAS signalling. NF1 mutations in neurofibromatosis cause loss of neurofibromin activity, resulting in hyperactivated RAS in patient cells and subsequent manifestation of symptoms. While our understanding of neurofibromin regulation has advanced in recent years, many questions regarding its meticulous control of RAS activity remain to be answered. Our objective is to find ways of increasing neurofibromin's GAP activity, thereby reducing levels of active RAS. NF1 mutations in a hotspot within the N-terminal domain of neurofibromin are known to cause severe phenotype disease. We propose that these mutations confer reduced protein stability. We hypothesize that re-stabilization of the mutant protein provides a therapeutic angle with which to treat severely affected patients, and understanding the pathways that degrade neurofibromin is key to developing this theory. We have identified that neurofibromin exists in an inactive homodimer conformation. Our objective is to understand how these dimers are regulated and how that contributes to neurofibromin activity. In line with this, we propose that activation of the receptor tyrosine kinase cKIT is an important factor in regulating neurofibromin/SPRED1 complexes: we will determine how activation of c-KIT affects neurofibromin GAP activity.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2022
- Accession Number
- AD1171256
Entities
People
- Frank P. Mccormick
Organizations
- University of California, San Francisco