Akt Pathway Activation by Human T-cell Leukemia Virus Type 1 Tax Oncoprotein.
Human T-cell leukemia virus (HTLV) type 1, the etiological agent of adult T-cell leukemia, expresses the viral oncoprotein Tax1. In contrast, HTLV-2, which expresses Tax2, is non-leukemogenic. One difference between these homologous proteins is the presence of a C-terminal PDZ domain-binding motif (PBM) in Tax1, previously reported to be important for non-canonical NFκB activation. In contrast, this study finds no defect in non-canonical NFκB activity by deletion of the Tax1 PBM. Instead, Tax1 PBM was found to be important for Akt activation. Tax1 attenuates the effects of negative regulators of the PI3K-Akt-mammalian target of rapamycin pathway, phosphatase and tensin homologue (PTEN), and PHLPP. Tax1 competes with PTEN for binding to DLG-1, unlike a PBM deletion mutant of Tax1. Forced membrane expression of PTEN or PHLPP overcame the effects of Tax1, as measured by levels of Akt phosphorylation, and rates of Akt dephosphorylation. The current findings suggest that Akt activation may explain the differences in transforming activity of HTLV-1 and -2.
From the Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 and.
Mathew A
MA
Cherian
From the Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 and.
Hicham H
HH
Baydoun
the Center for Retrovirus Research and Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210.
Jacob
J
Al-Saleem
the Center for Retrovirus Research and Departments of Pharmaceutics and Pharmaceutical Chemistry and.
Nikoloz
N
Shkriabai
the Center for Retrovirus Research and Departments of Pharmaceutics and Pharmaceutical Chemistry and.
Mamuka
M
Kvaratskhelia
the Center for Retrovirus Research and Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210.
Patrick
P
Green
From the Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 and lratner@dom.wustl.edu.
Lee
L
Ratner
D000595:Amino Acid Sequence; D004789:Enzyme Activation; D016356:Gene Products, tax / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
D016356:Gene Products, tax; D016328:NF-kappa B; C514970:tax protein, Human T-lymphotrophic virus 1; D051057:Proto-Oncogene Proteins c-akt
Akt PKB; PDZ domain; phosphatase and tensin homolog (PTEN); protein serine/threonine phosphatase (PSP); retrovirus