[Frontiers in Bioscience 17, 331-348, January 1, 2012]

WW domain-containing proteins: Retrospectives and the future

Zaidoun Salah1, Akram Alian1, Rami I. Aqeilan1

1The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel


1. Abstract
2. Introduction
3. Identification and classification of WW domain
3.1. WW domain structure
3.2. Tandemness of WW domains
4. WW domains function in different biological processes
4.1. Transcription
4.2. Apoptosis
4.2.1. YAP-p73 functional role in apoptosis
4.2.2. WWOX-p73 functional cross talk
4.3. Differentiation
4.4. Splicing
4.5. Ubiquitylation
5. WW domain proteins in tumorigenesis
5.1. Molecular and cellular function of tumor suppressor WWOX
5.2. YAP in cancer
5.3. ITCH as a proto-oncogene
6. The Hippo tumor suppressor pathway
7. WW domain proteins in other diseases
8. Concluding remarks and future perspective 9. Acknowledgments
10. References


WW domains are protein modules that mediate protein-protein interactions through recognition of proline-rich peptide motifs (PRM) and phosphorylated serine/threonine-proline sites. WW domains are found in many different structural and signaling proteins that are involved in a variety of cellular processes, including RNA transcription and processing, protein trafficking and stability, receptor signaling, and control of the cytoskeleton. WW domain-containing proteins and complexes have been implicated in major human diseases including cancer as well as in major signaling cascades such as the Hippo tumor suppressor pathway, making them targets for new diagnostics and therapeutics. In this review, we discuss how WW domains provide versatile platforms that link individual proteins into physiologically important networks and the indispensible role of WW domain-containing proteins in biology and pathology, especially tumorogenesis.