The Receptor Tyrosine Kinase FGFR4 Negatively Regulates NF-kappaB Signaling

NFκB signaling is of paramount importance in the regulation of apoptosis, proliferation, and inflammatory responses during human development and homeostasis, as well as in many human cancers. Receptor Tyrosine Kinases (RTKs), including the Fibroblast Growth Factor Receptors (FGFRs) are also important in development and disease. However, a direct relationship between growth factor signaling pathways and NFκB activation has not been previously described, although FGFs have been known to antagonize TNFα-induced apoptosis. assays. FGF19 stimulation of endogenous FGFR4 in TNFα-treated DU145 prostate cancer cells also leads to a decrease in IKKβ activity, concomitant reduction in NFκB nuclear localization, and reduced apoptosis. Microarray analysis demonstrates that FGF19 + TNFα treatment of DU145 cells, in comparison with TNFα alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NFκB signaling.These results identify a compelling link between FGFR4 signaling and the NFκB pathway, and reveal that FGFR4 activation leads to a negative effect on NFκB signaling including an inhibitory effect on proapoptotic signaling. We anticipate that this interaction between an RTK and a component of NFκB signaling will not be limited to FGFR4 alone

Multifunctional roles for MALT1 in T-cell activation

The activation of T cells is vital to the successful elimination of pathogens, but can also have a deleterious role in autoimmunity and transplant rejection. Various signalling pathways are triggered by the T-cell receptor; these have key roles in the control of the T-cell response and represent interesting targets for therapeutic immunomodulation. Recent findings define MALT1 (mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1) as a protein with proteolytic activity that controls T-cell activation by regulating key molecules in T-cell-receptor-induced signalling pathway

Casein kinase 1α governs antigen-receptor-induced NF-κB activation and human lymphoma cell survival

The transcription factor NF-κB is required for lymphocyte activation and proliferation as well as the survival of certain lymphoma types1, 2. Antigen receptor stimulation assembles an NF-κB activating platform containing the scaffold protein CARMA1/CARD11, the adaptor BCL10, and the paracaspase MALT1 (CBM complex), linked to the inhibitor of NF-κB kinase (IKK) complex3–12, but signal transduction is not fully understood1. We conducted parallel screens involving a mass spectrometry analysis of CARMA1 binding partners and an RNAi screen for growth inhibition of the CBM-dependent “activated B cell-like” (ABC) subtype of diffuse large B-cell lymphoma (DLBCL)12. Here, we report that both screens identified casein kinase 1α (CK1α) as a bifunctional regulator of NF-κB. CK1α dynamically associates with the CBM complex upon T cell receptor (TCR) engagement to augment cytokine production and lymphocyte proliferation. However, CK1α kinase activity plays a counterposing role by subsequently promoting the phosphorylation and inactivation of CARMA1. CK1α has thus a dual “gating” function which first promotes and then terminates receptor-induced NF-κB. ABC DLBCL cells required CK1α for constitutive NF-κB activity indicating that CK1α functions as a “conditionally essential malignancy” (CEMal) gene - a member of a new class of potential cancer therapeutic targets