Submitted July 8, 2008
Accepted April 13, 2009
TGF-
induces degradation of TAL1/SCL by the ubiquitin-proteasome pathway through AKT-mediated phosphorylation
Jean-Michel Terme, Ludovic Lhermitte, Vahid Asnafi, and Pierre Jalinot*
Laboratoire de Biologie Moleculaire de la Cellule, UMR5239 CNRS / ENS de Lyon, Lyon, France
Universite Paris 5 Descartes, UMR 8147 CNRS, Assistance Publique-Hopitaux de Paris (AP-HP) Hopital Necker-Enfants-Malades / Hematology department, Paris, France
* Corresponding author; email: pjalinot{at}ens-lyon.fr.
TAL1 (T-cell acute lymphoblastic leukemia 1), also known as stem cell leukemia (SCL), plays important roles in differentiation of hematopoietic and endothelial cells and is deregulated in a high percentage of T-cell acute lymphoblastic leukemia (T-ALL). In this report we show that the intracellular concentration of TAL1 is regulated by transforming growth factor 
(TGF-) which triggers its polyubiquitylation and degradation by the proteasome. This effect is mediated by AKT1 which phosphorylates TAL1 at threonine 90. Immunoprecipitation experiments showed that this event increases association of TAL1 with the E3 ubiquitin ligase CHIP. The E47 heterodimerization partner of TAL1 hinders this association. Our observations indicate that activation of the TGF- and PI3K/AKT pathways might reverse overexpression of TAL1 in leukemic cells by inducing proteolysis of this important oncogene.
