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Raf-like Ras/Rap-binding domains in RGS12- and still-life-like signalling proteins
1National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20814, USA. Ponting@ncbi.nlm.nih.gov
Abstract:
Ras proteins play critical roles in regulating cell growth and differentiation, and mutated Ras genes are expressed in a variety of human cancers. Consequently, much interest has centered on the binding partners of Ras, including the Ras-binding domain (RBD) of Raf kinase. Here evidence is presented that domains homologous to the Raf RBD are present in tandem in RGS12, RGS14 and LOCO, and singly in molecules similar to mouse Tiam-1. In addition, RGS12, RGS14 and LOCO are shown to contain single "LGN motifs" that are guanine nucleotide exchange factors specific for the alpha-subunit of G proteins. These findings indicate "cross-talk" interactions between signalling pathways involving Ras and Rap and pathways involving Rho, Rac and G alpha GTPases.
Insights
This study identifies novel Ras-binding domains in RGS12, RGS14, and LOCO proteins, revealing cross-talk between Ras and G protein signaling pathways crucial for cell growth and cancer.
Area of Science:
- Molecular Biology
- Cell Signaling
- Biochemistry
Background:
- Ras proteins are key regulators of cell growth and differentiation.
- Mutated Ras genes are implicated in various human cancers.
- The Ras-binding domain (RBD) of Raf kinase is a known Ras interaction partner.
Purpose of the Study:
- To identify novel Ras-binding proteins.
- To investigate potential cross-talk between Ras signaling and other GTPase pathways.
Main Methods:
- Bioinformatic analysis to identify homologous domains.
- Protein domain analysis.
Main Results:
- Domains homologous to the Raf RBD were found in RGS12, RGS14, and LOCO.
- These proteins also contain LGN motifs, which are guanine nucleotide exchange factors for G protein alpha-subunits.
- Homologous RBDs were also identified in molecules similar to mouse Tiam-1.
Conclusions:
- RGS12, RGS14, and LOCO possess domains that interact with Ras.
- These proteins link Ras/Rap signaling with Rho, Rac, and G alpha GTPase pathways.
- This suggests complex cross-talk between these critical signaling networks.