[Frontiers in Bioscience 7, d1782-1797, August 1, 2002]

THE ROLE OF SSeCKS/Gravin/AKAP12 SCAFFOLDING PROTEINS IN THE SPACIOTEMPORAL CONTROL OF SIGNALING PATHWAYS IN ONCOGENESIS AND DEVELOPMENT

Irwin H. Gelman

Dept. of Medicine & Ruttenberg Cancer Center, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, NY

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. SSeCKS as a tumor suppressor
4. SSeCKS as a mitogenic regulator
5. Control of cytoskeletal architecture by SSeCKS
6. SSeCKS and Gravin: orthologues
7. SSeCKS/Gravin orthologues
8. Transcriptional control of SSeCKS
9. SSeCKS/Gravin protein products
10. SSeCKS as a PKC and PTK substrate
11. Protein motifs and binding partners
12. Developmental, tissue and sub-cellular expression of SSeCKS/Gravin
13. Unanswered questions.
14. Perspective
15. Acknowledgments
16. References

1. ABSTRACT

Scaffolding proteins are thought to facilitate the efficiency and specificity of enzyme/substrate reactions by coordinating their interaction along a cytoskeletal infrastructure in a spacial and temporal manner. Rodent SSeCKS, and its human orthologue, Gravin, seem to function as tumor suppressors and regulators of mitogenesis, inflammatory response, development and differentiation via novel scaffolding functions involving the selective binding of key G1à S phase signaling proteins such as protein kinase C (PKC), PKA, calmodulin, cyclins and β-adrenergic receptors. The association of SSeCKS/Gravin with the actin-based cytoskeleton as well as to plasma membrane sites via N-terminal myristylation places these proteins at the junction of signaling and cytoskeletal pathways. The following review describes the regulatory and scaffolding functions of SSeCKS and Gravin and how mitogen-induced phosphorylation modulates their ability to regulate cell adhesion, signaling, mitogenesis and oncogenesis.