Modulation of cell survival by prohibitin and IAP-IAP complexes
Final Report Abstract
The Emmy Noether tenure led to the elucidation of novel components of the key signaling machinery that drives fundamental cellular process like cell death, migration and differentiation. First, we have confirmed our observations that the plasma membrane associated fraction of prohibitin is directly involved in the activation of a key signaling molecule CRAF kinase in tumour cells. This study has proposed that targeting prohibitin- CRAF interface could possibly be a strategy to combat RAS-mediated tumourigenesis. Importantly, the natural anti-tumour drugs Rocaglamide target this interaction and thus opening up a novel avenue for tumour therapeutics. We have also made some important contributions to the fundamental understanding of a key signaling pathway, the RAS-RAF- MAPK pathway. We identified that RAF isoforms compete for their interaction with their downstream kinase target MEK1 and that the RAF dimer interface is also exploited for this key interaction. These results are important for developing rational therapeutics targeting the RAF-MAPK pathway. Apart from the RAF-MAPK, we have focused on the inhibitors of Apoptosis proteins (IAPs) which are shown to inhibit apoptosis by directly binding to caspases. We have unveiled the other side of these molecules and discovered that IAPs also regulate cell shape, migration and cellular differentiation. These studies have enhanced our current understanding of how IAPs work and thus enabled us to adroitly administer IAP-based cancer therapeutics. We have also identified how Ubiquitin signaling contributes to kinase inactivation and cell shape changes during migration which are also seen as a major conceptual advancements as revealed by the highlights and commentaries garnered in various places including in Nature reviews Molecular Cell Biology, EMBOJ, Faculty of 1000 and has also gained the attention of the general media.
Publications
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(2008) Mcl-1 is a key regular of apoptosis resistance in Chlamydia trachomatis infected cells. PloS ONE 3(9):e3102
Krishnaraj Rajalingam, Manu Sharma, Christine Wolkewitz, Monique Oswald, Christopher J. Froelich, Thomas Rudel
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(2008) X linked and cellular IAPs modulate the stability of C-RAF kinase and cell motility. Nature Cell Biology 10(12): 1447-55
Taner Dogan, Gregory S.Harms, Mirko Hekman, Christiaan Karremann, Tripat kaur Oberoi, Emad S.Alnemri, Ulf R Rapp, Krishnaraj Rajalingam
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(2009) Regulation of RAF Activity by 14-3-3 Proteins –RAF Kinases Associate Functionally with both Homo- and Heterodimeric forms of 14-3-3 Proteins. J Biol Chem 30;284(5):3183-94.2010
Andreas Fischer, Angela Baljuls, Jörg Reinders, Elena Nekhoroshkova, Claudi Sibilski, Renate Metz, Stefan Albert, Krishnaraj Rajalingam, Mirko Hekman, and Ulf R. Rapp
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(2009) The C-terminus of p63 Contains Multiple Regulatory Elements with Different Functions. Cell death &Disease 1, e5
Wesley E. Straub, Tobias A. Weber, Birgit Schäfer, Eleonora Candi, Florian Durst, Horng Der Ou, Jan Heering, Krishnaraj Rajalingam, Gerry Melino and Volker Dötsch
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(2011) Inhibitor of Apoptosis proteins regulate the plasticity cell migration by directly targeting Rac1 for degradation. EMBO J. 31(1):14-28
Tripat Kaur Oberoi, Taner Dogan, Jennifer C.Hocking, Rolf-Peter Scholz, Juliane Mooz, Carrie L Anderson, Christiaan Karreman, Dagmar Meyer zu Heringdorf, Gudula Schmidt, Mika Ruonala, Kazuhiko Namikawa, Gregory S Harms, Alejandro Carpy, Boris Macek, Reinhard W Koester and Krishnaraj Rajalingam
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(2011). Immune modulation by Fas Ligand reverse Signaling: Lymphocyte proliferation is attenuated by the intracellular Fas Ligand domain. Blood 117(2): 519-29
Katharina Lückerath, Vladimir Kirkin, Inga Maria Melzer, Frederic Thalheimer, Dagmar Siele, Wiebke Milani, Thure Adler, Antonio Aguilar-Pimentel, Marion Horsch, Geert Michel, Johannes Beckers, Dirk H. Busch, Markus Ollert, Valerie Gailus- Durner, Helmut Fuchs, Martin Hrab! de Angelis, Frank J. T. Staal, Krishnaraj Rajalingam, Lothar J. Strobl, Ursula Zimber-Strobl and Martin Zörnig
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(2012) Caspase-2 is an initiator caspase responsible for pore forming toxin-mediated apoptosis. EMBOJ. 31(11):2615-28
Gergely Imre, Jan Heering, Armelle-Natsuo Takeda, Matthias Husmann, Bernd Thiede, Dagmar Meyer zu Heringdorf, Douglas R Green, F. Gisou van der Goot, Bhanu Sinha, Volker Dötsch, Krishnaraj Rajalingam
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(2012) Role of melanoma inhibitor of apoptosis (ML-IAP), a member of baculoviral IAP repeat (BIR) domain family in the regulation of C-RAF kinase and cell migration. J Biol Chem. 2012 Jun 18 [Epub ahead of print]
Tripat Kaur Oberoi-Khanuja, Christiaan Karreman, Sarit Larisch, Ulf Rapp, Krishnaraj Rajalingam
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(2012) Sorafenib-induced mitochondrial complex I inactivation and cell death in human neuroblastoma cells J.Proteome.Res. 11(3):1609-20
Vibeke Hervik Bull, Krishnaraj Rajalingam, Bernd Thiede
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(2013) Identification of non-canonical NF-"B signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells. Cell Death Dis. 28;4:e564
Aurélie Tchoghandjian, Claudia Jennewein, Ines Eckhardt, Krishnaraj Rajalingam, Simone Fulda
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(2013) Novel oncogenic ERBB3 mutations in human cancers. Cancer Cell 23(5):603-17
Bijay S. Jaiswal, Noelyn M. Kljavin, Eric Stawiski, Emily Chan, Chaitali Parikh, Steffen Durinck, Subhra Chaudhuri, Kanan Pujara, Joseph Guillory, Kyle A. Edgar, Vasantharajan Janakiraman, Rolf-Peter Scholz, Krista K Bowman, Maria Lorenzo, Hong Li, Jiansheng Wu, Wenlin Yuan, Brock A. Peters, Zhengyan Kan, Jeremy Stinson, Michelle Mak, Zora Modrusan, Charles Eigenbrot, Ron Firestein, Howard M. Stern, Krishnaraj Rajalingam, Gabriele Schaefer, Mark A. Merchant, Mark X. Sliwkowski, Frederic J. de Sauvage and Somasekar Seshagiri
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(2014) Dimerization of ARAF promotes MAPK activation and cell migration. Sci. Signal. 5;7(337):ra73
Juliane Mooz, Tripat Kaur Oberoi-Khanuja, Gregory S Harms, Weiru Wang, Bijay S Jaiswal, Somasekar Seshagiri, Ritva Tikkanen, Krishnaraj Rajalingam
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(2014) Ubiquitin dependent regulation of MEKK2/3- MEK5-ERK5signaling module by XIAP and cIAP1. EMBOJ 33(16):1784-801
Armelle-Natsuo Takeda1, Tripat Kaur Oberoi-Khanuja, Gabor Glatz, Katharina Schulenberg, Rolf Peter-Scholz, Alejandro Carpy, Boris Macek, Attila Remenyi, Krishnaraj Rajalingam
