05-954 Sigma-AldrichAnti-TCL1 Antibody

Chromosomal translocations leading to overexpression of p14(TCL1) and its homologue p13(MTCP1) are hallmarks of several human T-cell malignancies (1). p14(TCL1)/p13(MTCP1) co-activate protein kinase B (PKB, also named Akt) by binding to its pleckstrin homology (PH) domain, suggesting that p14(TCL1)/p13(MTCP1) induce T-cell leukemia by promoting anti-apoptotic signals via PKB (2, 3). Here we combined fluorescence anisotropy, NMR, and small angle x-ray-scattering measurements to determine the affinities, molecular interfaces, and low resolution structure of the complex formed between PKBbeta-PH and p14(TCL1)/p13(MTCP1). We show that p14(TCL1)/p13(MTCP1) target PKB-PH at a site that has not yet been observed in PH-protein interactions. Located opposite the phospholipid binding pocket and distal from known protein-protein interaction sites on PH domains, the binding of dimeric TCL1 proteins to this site would allow the crosslinking of two PKB molecules at the cellular membrane in a preactivated conformation without disrupting certain PH-ligand interactions. Thus this interaction could serve to strengthen membrane association, promote trans-phosphorylation, hinder deactivation of PKB, and involve PKB in a multi-protein complex, explaining the array of known effects of TCL1. The binding sites on both proteins present attractive drug targets against leukemia caused by TCL1 proteins.

The protein product of the T-cell leukemia/lymphoma 1 (TCL1) oncogene was recently identified as a novel Akt kinase activator. Its crystal structure predicts regions most likely involved in protein-protein interactions, and complex formation is required for TCL1 to activate Akt. TCL1 is expressed in a broad range of normal and malignant lymphoid cell types and in a high proportion of testicular seminomas of germ cell origin, indicating its potential to serve as a novel anti-cancer drug target. This review is focused on the current state of knowledge of TCL1 and the medical implications of its discovery.

Members of the TCL1 family of oncogenes are abnormally expressed in mature T-cell leukemias and B-cell lymphomas. The proteins are involved in the coactivation of protein kinase B (Akt/PKB), a key intracellular kinase. The sequences and crystal structures of three Tcl1 proteins were analyzed in order to understand their interactions with Akt/PKB and the implications for lymphocyte malignancies. Tcl1 proteins are approximately 15 kD and share 25-80% amino acid sequence identity. The tertiary structures of mouse Tcl1, human Tcl1, and Mtcp1 are very similar. Analysis of the structures revealed conserved semi-planar surfaces that have characteristics of surfaces involved in protein-protein interactions. The Tcl1 proteins show differences in surface charge distribution and oligomeric state suggesting that they do not interact in the same way with Akt/PKB and other cellular protein(s).