[Frontiers in Bioscience 17, 1-15, January 1, 2012]

MDA-9/syntenin: a positive gatekeeper of melanoma metastasis

Swadesh K. Das1, Sujit K. Bhutia1, Timothy P. Kegelman1, Leyla Peachy1, Regina A. Oyesanya1, Santanu Dasgupta1, Upneet K. Sokhi1, Belal Azab1, Rupesh Dash1, Bridget A. Quinn1, Keetae Kim1, Paola M. Barral1, Zhao-zhong Su1, Habib Boukerche2, Devanand Sarkar1,3,4, Paul B. Fisher1,3,4

1Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, 2INSERM U583, Montpellier, France, 3VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, 4VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Cloning of mda-9/syntenin
4. Structure and regulation of mda-9/syntenin
5. MDA-9/syntenin as a positive regulator of tumor metastasis
5.1. MDA-9/syntenin and metastatic melanoma
5.2. MDA-9/syntenin interacts with c-Src through PDZ domains
5.3. Binding with c-Src, MDA-9/syntenin facilitates assembly of c-Src/FAK complexes
5.4. MDA-9/syntenin stimulates activation of pro-MMP-2 in melanoma
5.5. MDA-9/syntenin-mediated FAK/Src activation-induced metastasis
5.6. MDA-9/Syntenin and metastasis in the context of other malignancies
6. MDA-9/syntenin acts as a multifunctional intracellular adapter protein
6.1. MDA-9/syntenin regulates syndecan recycling
6.2. MDA-9/syntenin and pro-TGFα transport
6.3. MDA-9/syntenin and Delta 1: impact in Notch signaling
6.4. MDA-9/syntenin: role in tetraspanins internalization
6.5. MDA-9/syntenin and regulation of the nervous system through control of synaptic integrity
6.6. MDA-9/syntenin and epherins: involvement in presynaptic development
6.7. Regulation of glutamate signaling: role of MDA-9/syntenin
6.8. MDA-9/syntenin and axon outgrowth
6.9. MDA-9/syntenin and Interleukin-5 signaling
7. MDA-9/syntenin as a tumor suppressor
8. Conclusions and Future perspectives
9. Acknowledgements
10. References

1. ABSTRACT

Melanoma differentiation associated gene-9 (MDA-9), synonymous with syntenin, is an adapter protein that provides a central role in regulating cell-cell and cell-matrix adhesion. MDA-9/syntenin transduces signals from the cell-surface to the interior through its interaction with a plethora of additional proteins and actively participates in intracellular trafficking and cell-surface targeting, synaptic transmission, and axonal outgrowth. Recent studies demarcate a seminal role of MDA-9/syntenin in cancer metastasis. In the context of melanoma, MDA-9/syntenin functions as a positive regulator of melanoma progression and metastasis through interactions with c-Src and promotes the formation of an active FAK/c-Src signaling complex leading to NF-k B and matrix metalloproteinase (MMP) activation. The present review provides a current perspective of our understanding of the important features of MDA-9/syntenin and its significant role in tumor cell metastasis with special focus on molecular mechanism of action.