TCL1-family proteins are 13�C15 kDa non-enzymatic interaction modules. Their restricted physiological expression and apparent. Normal time- and tissue-restricted expression of TCL1 genes is important for efficient fertility, and the development of T and B cell lineages. Deregulation of TCL1 expression can cause the transformation of mature human T and B lymphocytes, and is associated with a variety of human diseases, including VE-821 1232410-49-9 T-cell prolymphocytic leukaemia, B-cell chronic leukaemia, B-cell lymphoma and germ-cell tumours ]. TCL1A is a co-activator of AKT, a serine/threonine protein kinase that regulates many cellular processes, including proliferation and survival. TCL1A forms homodimers, and each protomer binds one pleckstrin homology domain of AKT. Co-activation may thus result from stabilising AKT in an open conformation, from promoting AKT auto-phosphorylation in trans, and/or from reinforcing AKT attachment to the membrane, where its effectors are located. Activated AKT can promote cell survival by phosphorylating downstream targets such as BAD. AKT can also activate the NF-kB transcription factor, possibly by phosphorylating the IkB kinase. Phosphorylated IKK phosphorylates IkB, leading to dissociation of the IkB:NF-kB complex. Liberated NF-kB subsequently translocates to the nucleus to activate survival-inducing genes. However, the effects of TCL1A on AKT are insufficient to fully explain TCL1A oncogenesis. For example, AKT phosphorylation or inactivation kinetics do not consistently relate to TCL1A expression in both transgenic mice and patient�Cderived neoplasia, and AKT activation alone does not necessarily cause tumours in B cells. This suggests that additional effects, and effectors, of TCL1A exist. Recently, it was reported that the NF-kB pathway is important for B-CLL in transgenic mouse models, and that TCL1A activates NF-kB through an AKTindependent route. Corroborating an AKT-independent targeting of NF-kB by TCL1A, we here report that TCL1A binds directly to the NF-kB inhibitor IkB. Several lines of evidence suggest an AKT-independent action of TCL1A on NF-kB pathways. We here sharpened this picture by showing that TCL1A and the NF-kB inhibitor IkB associate in vitro, in yeast-two-hybrid systems, and when transiently overexpressed in 293 cells. We also showed in vitro that TCL1A competed with NF-kB for binding to IkB, suggesting that TCL1A interferes with the inhibitory interaction between IkB and NF-kB. Since TCL1A binds to the same first two ankyrin repeats of IkB which also interact with helices aA and aB of RELA, it is likely that TLC1A and RELA use overlapping binding sites on IkB. However, we can not exclude that IkB binding to one partner causes conformational changes that affect allosterically the binding site of the other partner. On a cellular level, the effect expected to arise from the competition of TCL1A and NF-kB for I kB would be an AKTindependent NF-kB-activation by TCL1A. This was indeed recently observed by Pekarsky et al.. These authors reported that this effect involves the association between TCL1A and p300. The molecular details of the association between TCL1A and p300 remain elusive. Since both proteins are multivalent adaptor proteins, sequential or concomitant interactions of TCL1A with IkB are not excluded, and may be necessary for activation of NF-kB. The description of several AKT-independent TCL1A targets suggests that TCL1A affects a number of alternative and interconnected signalling pathways. Indeed, depending on the cell type and PF-04217903 experimental conditions, both NF-kB activation and inhibition by TCL1A were reported, as well as alternative, NF-kB independent routes. Thus, TCL1A increasingly appears as a polyvalent adaptor protein, whose cellular action is dramatically affected by its sub-cellular concentration and the availability of potential targets. The affinity we measured between IkB and TCL1A was about 1,000 fold weaker than the one previously reported between IkB and NF-kB.