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A Modeled Hydrophobic Domain on the TCL1 Oncoprotein Mediates Association with AKT at the Cytoplasmic Membrane

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Department of Pathology and Laboratory Medicine, Microbiology and Immunology, UCLA-DOE Laboratory of Structural Biology and Molecular Medicine, Molecular Biology Institute and UCLA AIDS Institute, UCLA School of Medicine, Los Angeles, California 90095−1732
Cite this: Biochemistry 2002, 41, 20, 6376–6382
Publication Date (Web):April 17, 2002
Copyright © 2002 American Chemical Society

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    AKT has a critical role in relaying cell survival and proliferation signals initiated by ligand binding to surface receptors in mammalian cells. Induction of AKT serine/threonine kinase activity is augmented by the T-cell leukemia-1 (TCL1) oncoprotein through a physical association requiring the AKT pleckstrin homology domain. Here, we used molecular modeling and identified an exposed hydrophobic patch composed of two discontinuous amino acid stretches near one end of the TCL1 β-barrel that was required for a TCL1−AKT association. Site-directed mutations of this region did not affect TCL1 secondary structure, yet they disrupted interactions with AKT. This region was found in other members of the TCL1 oncoprotein family, such as TCL1b and MTCP1, and suggested a conserved, novel AKT binding domain. Interestingly, TCL1 and AKT co-localize in multiple cell compartments, but only extracts from the plasma membrane stimulate optimal complex formation in vitro. Identification of an AKT binding domain on TCL1 is an important step in deciphering the complex interactions that regulate AKT kinase activity in lymphocyte development and neoplasia within the immune system.

     This work was supported by an Amgen/UC BioStar Award (S98-35 to M.A.T.), a UCLA CFAR Award (S.W.F. and M.A.T.), the Lymphoma Research Foundation of America (M.A.T.), a PHSNS Award (T32-CA09056 to C.S.M.), and the National Institutes of Health (GM40185 to P.M. and CA74929 to M.A.T.).

     Department of Pathology and Laboratory Medicine.


     Microbiology and Immunology.

     UCLA-DOE Laboratory of Structural Biology and Molecular Medicine.


     To whom correspondence should be addressed:  Department of Pathology and Laboratory Medicine, UCLA School of Medicine, MacDonald Research Laboratories, Room 4-760, 675 Charles E. Young Drive South, Los Angeles, CA 90095-1732. Telephone:  310-206-6754. Fax:  310-267-0382. E-mail:  [email protected].


     Molecular Biology Institute.

     UCLA AIDS Institute.

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