[Frontiers in Bioscience 7, d288-294, January 1, 2002]

AUTOINHIBITION OF SOS BY INTRAMOLECULAR INTERACTIONS

Brian E. Hall 2, Shao-Song Yang 3, Dafna Bar-Sagi 1

1 Department of Molecular Genetics and Microbiology and the Graduate Programs in 2 Molecular Pharmacology and 3 Molecular and Cellular Biology, State University of New York at Stony Brook, Stony Brook, New York 11794-5222

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Sos domain structure
3.1. The catalytic core
3.2. The N-terminal region
3.3. The C-terminal region
4. Evidence for Sos regulation by intramolecular interactions
5. Evidence for a suppressive role of the C-terminal region
6. Possible mechanisms of autoinhibition by the C-terminal region
6.1. Regulation of Ras-Sos binding
6.2. Regulation by Grb2 binding
6.3. Regulation of membrane targeting
6.4. Regulation by phosphorylation
6.5. Regulation by interaction with other factors
7. Evidence for a suppressive role of the N-terminal region
8. Possible mechanisms of autoinhibition by the N-terminal region
Regulation of Ras-Sos binding
DH-domain-dependent intramolecular interactions
9. Cooperative N- and C-terminal regulation of Sos catalytic activity
10.Conclusions and implications
11. Acknowledgements
12. References

1. ABSTRACT

Sos proteins function as activators of Ras signaling by catalyzing guanine nucleotide exchange on Ras. Sos regulation was initially thought to be accomplished primarily through its growth factor-dependent recruitment to the plasma membrane. More recent data has indicated that while membrane association is an indispensable means of Sos regulation, additional mechanisms involving intramolecular interactions function to control Sos activity towards Ras. This review will examine the experimental evidence for Sos intramolecular interactions and their contribution to Sos regulation.