This project addresses the functional relevance of the hematopoiesis-specific Rho GTPase RhoH, which is overexpressed in primary human chronic lymphocytic leukemia (CLL) cells, and accelerates the accumulation of leukemic cells in peripheral blood and the development of the leukemic burden in lymphoid tissues in a murine model of CLL. Structure-function-analysis will be performed of the inhibitory interaction between RhoH and inositol-phospholipid-specific phospholipase C-γ2 (PLCγ2) and the interaction between RhoH and Syk family protein tyrosine kinases such as ZAP70. The results will be taken to construct signaling-biased RhoH mutants capable of selectively interacting with either PLCγ2 or ZAP70 in cultured B cells in vitro and in a murine CLL model in vivo.
Pfreimer M, Vatter P, Langer T, Wieland T, Gierschik P, Moepps B. LARG links histamine-H1-receptoractivated Gq to Rho-GTPase-dependent signaling pathways. Cell Signal. 2012;24:652-63.
Everett KL, Buehler A, Bunney TD, Margineanu A, Baxendale RW, Vatter P, Retlich M, Walliser C, Manning HB, Neil MA, Dunsby C, French PM, Gierschik P, Katan M. Membrane environment exerts an important influence on Rac-mediated activation of phospholipase C-γ2. Mol Cell Biol. 2011;31:1240-51.
Gutman O*, Walliser C*, Piechulek T, Gierschik P*, Henis YI*. Differential regulation of phospholipase C-β2 activity and membrane interaction by Gαq, Gβ1γ2, and Rac2. J Biol Chem. 2010;285:3905-15. *Shared first and last authorships.
Bunney TD, Opaleye O, Roe SM, Vatter P, Baxendale RW, Walliser C, Everett KL, Josephs MB, Christow C, Rodrigues-Lima F, Gierschik P, Pearl LH, Katan M. Structural insights into formation of an active signaling complex between Rac and phospholipase C-γ2. Mol Cell. 2009;34:223-33.
Walliser C, Retlich M, Harris R, Everett KL, Josephs MB, Vatter P, Esposito D, Driscoll PC, Katan M, Gierschik P, Bunney TD. Rac regulates its effector phospholipase Cγ2 through interaction with a split pleckstrin homology domain. J Biol Chem. 2008;283:30351-62.
Bunney TD, Harris R, Gandarillas NL, Josephs MB, Roe SM, Sorli SC, Paterson HF, Rodrigues-Lima F, Esposito D, Ponting CP, Gierschik P, Pearl LH, Driscoll PC, Katan M. Structural and mechanistic insights into ras association domains of phospholipase C epsilon. Mol Cell. 2006;21:495-507.
Dreissigacker U, Mueller MS, Unger M, Siegert P, Genze F, Gierschik P, Giehl K. Oncogenic K-Ras downregulates Rac1 and RhoA activity and enhances migration and invasion of pancreatic carcinoma cells through activation of p38. Cell Signal. 2006;18:1156-68.
Piechulek T, Rehlen T, Walliser C, Vatter P, Moepps B, Gierschik P. Isozyme-specific stimulation of phospholipase C-γ2 by Rac GTPases. J Biol Chem. 2005;280:38923-31.