[Frontiers in Bioscience 15, 1150-1163, June 1, 2010] 1150 Interactions between PrP c and other ligands with the 37-kDa/67-kDa laminin receptor Vusi Mbazima, Bianca Da Costa Dias, Aadilah Omar, Katarina Jovanovic, Stefan F T Weiss School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits 2050, Johannesburg, Republic of South Africa (RSA) TABLE OF CONTENTS 1. Abstract 2. The 37-kDa/67-kDa LRP/LR reveals a multifunctional protein 3. The 37-kDa/67-kDa LRP/LR and its influence on prion and zoonotic diseases 4. The role of prion proteins and the 37-kDa/67-kDa LRP/LR in signal transduction and cell cycle 5. Employing antibodies directed against 37-kDa/67-kDa LRP/LR as therapeutic tools for prion diseases 6. Pentosan polysulfate in the treatment of prion diseases 7. Therapeutic interventions utilizing RNA interference for prion disease treatment 8. LRP102-295 mutant as a decoy receptor for the treatment of prion disorders 9. Other strategies for prion disease therapy 10. The role of the prion protein and its receptor in other neurodegenerative diseases 11. 37-kDa/67-kDa LRP/LR and cancer 12. 37-kDa/67-kDa LRP/LR and Viral Diseases 13. Perspective 14. Acknowledgements 15. References 1. ABSTRACT The 37-kDa/67 kDa laminin receptor (LRP/LR) represents a multifunctional protein. It is a receptor for viruses such as Dengue Viruses, Alphaviruses and Adeno- associated-Viruses (AAV), as well as the cellular prion protein (PrP c ) and infectious prions (PrP Sc ). The 37- kDa/67-kDa LRP/LR plays furthermore fundamental roles in basic cell biological processes such as cell adhesion and cell growth and acts as a key player in metastatic cancer, affecting invasion, adhesion and apoptotic processes. This review gives fundamental insights into basic cellular processes affected by LRP/LR including signal transduction and cell cycle progression and focuses on pathophysiological implications of the interaction of prion proteins, laminin, viruses and other ligands with LRP/LR affecting the development of highly-prevalent diseases such as cancer, neurodegenerative diseases such as prion disorders and Alzheimer’s Disease as well as viral infections. Molecular tools such as LRP/LR specific antibodies and siRNAs targeting LRP expression as possible alternative therapeutics for the treatment of neurodegenerative diseases, metastatic cancer and viral infections are emphasized. 2. THE 37-kDa/67-kDa LRP/LR REVEALS A MULTIFUNCTIONAL PROTEIN The 67-kDa laminin receptor (LR) is a non- integrin cell surface receptor with high affinity binding for its corresponding ligand, laminin, an extracellular matrix glycoprotein involved in cell growth, movement, attachment and differentiation (for review: (1-4)). Laminin interacts with the 67-kDa LR via two binding domains; the first domain is known as the peptide G sequence which is located between amino acids 161-180 and the second laminin binding domain is located between amino acids 205-229 at the C-terminal of the 37-kDa LRP (5). Besides having high affinity for laminin, 67-kDa LR also acts as a receptor for other extracellular matrix molecules such as elastin and carbohydrates (1). Furthermore, 67-kDa LR is reported to mediate laminin-induced tumor cell growth, migration, invasiveness and metastasis (6, 7) . This is due to the high laminin receptor levels found in a number of cancer types which correlates with an increase in the invasiveness and metastasis of tumor cells (8, 9). The relationship between the 67 kDa high affinity receptor (LR) and the 37-kDa laminin receptor precursor (LRP), is poorly understood. Several reports suggest that 67-kDa LR