Targeting CD4 to disrupt signaling through membrane rafts: Towards a raft-based therapeutics Myriam Chentouf, Maxime Rigo, Andre Pelegrin, Thierry Chardes Immunology Endocrine and Metabolic Agents in Medicinal Chemistry, 2008 Membrane rafts, due to the presence of several immunoreceptors, signal-transducing kinases and lipids such as ceramides which can act as second messengers, play a crucial role in the cell signaling network which fine-tunes various biological effects. The ability of membrane rafts to segregate receptors provides a mechanism for compartmentalization of signaling molecules in plasma membrane by concentrating some components in membrane rafts and excluding others. Based on these observations, the concept of raft-based therapeutics has recently emerged. Raft-targeting molecules can modulate the lipid-protein rheostat of membrane rafts to treat various diseases, such as cancer, neurological disorders or infectious diseases. In this review, we focus on membrane rafts as "discrete" organizing elements of T lymphocytes' plasma membrane and how to reconcile the dynamic nature of membrane rafts with the formation of the immunological synapse. We describe CD4-specific antibodies as prototypical modulators for the disruption of the lipid-protein rheostat in membrane rafts and extend the concept of raft-based therapeutics to other antibodies, sterol- and sphingolipid-modulating drugs, glycerophospholipid analogs, fatty acid modulators, and peptide-derived molecules. This review highlights a novel mode of action of drugs through dietary or therapeutic interventions that target membrane rafts.
PKC ζ-mTOR pathway: A new target for rituximab therapy in follicular lymphoma Ludivine Leseux, Guy Laurent, Camille Laurent, Maxime Rigo, Amandine Blanc, et al. Blood, 2008 Previous studies have documented that, in malignant B cells, rituximab elicits a complex and not yet totally understood signaling network contributing to its antitumor effect. In this context, we investigated the role of protein kinase C ζ (PKCζ), an atypical PKC isoform, in the cellular response to rituximab. We found that follicular lymphoma cells displayed an increase in PKCζ expression and activity levels, compared with nonmalignant B cells, and that this enzyme was a critical regulator of the classical MAPK module by stimulating Raf-1 kinase activity. PKCζ appeared to be a significant contributor of abnormal mTOR regulation in follicular lymphoma cells through a MAPK-dependent mechanism. Rituximab was found to inhibit the PKCζ/MAPK/mTOR module in these cells but not in other B-cell lymphomas. Importantly, the expression of a constitutively active form of PKCζ resulted in an efficient protection of these cells toward rituximab. Altogether, our study describes a new regulatory component of mTOR pathway in follicular cell lymphoma and demonstrates that PKCζ is a target for rituximab. Therefore, PKCζ could represent an important parameter for rituximab efficacy and a promising target for future targeted therapy in follicular lymphoma.
