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Am J Transl Res 2010;2(1):19-42
Review Article
Physiological regulation of Akt activity and stability
Yong Liao, Mien-Chie Hung
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515
Holcombe Blvd., TX 77030, USA; Department of Molecular & Cellular Oncology, The University of Texas M.D.
Anderson Cancer Center, 1515 Holcombe Blvd., TX 77030, USA; and Center for Molecular Medicine and Graduate
Institute of Cancer Biology, China Medical University and Hospital, Taichung 404, Taiwan
Received November 2, 2009; accepted November 3, 2009; available online January 11, 2010
Abstract: The serine/threonine protein kinase B (PKB, also known as Akt) constitutes an important node in
diverse signaling cascades downstream of growth factor receptor tyrosine kinases. Akt plays an essential role in
cell survival, growth, migration, proliferation, polarity, and metabolism (lipid and glucose); cell cycle progression;
muscle and cardiomyocyte contractility; angiogenesis; and self-renewal of stem cells. Altered Akt activity has been
associated with cancer and other disease conditions, such as diabetes mellitus, neurodegenerative diseases,
and muscle hypotrophy. In the past decade, the upstream signals that lead to Akt activation, the downstream
substrates that exert the effects of Akt, and the secondary binding proteins that regulate Akt activation have been
well documented. Recent reports from our group and others have revealed how the stability of Akt protein is
regulated through phosphorylation on its Thr-Pro motifs. This literature review details findings of those reports
and others relevant to the regulation of Akt activation by its upstream kinases, with a focus on mammalian target
of rapamycin complexes (mTORCs) and inactivation by PHLDA3 and the protein phosphatases PP2A and
pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP). Reports on ubiquitin-dependent
Akt degradation, caspase-dependent cleavage, and the role of molecular chaperone heat shock protein 90
(Hsp90) in the regulation of Akt stability are summarized. The highlight will be on the role of “turn motif”
phosphorylation and an isomerase, Pin1, in the regulation of Akt stability. We also discuss issues related to the
intricate mTORC2-Akt-mTORC1 loop and the contradictory regulation of Akt phosphorylation and stabilization of
Akt by mTORC2. Finally, we offer perspective on potential future directions for investigation, particularly on
translating the knowledge we learned on the regulation of Akt stability into therapeutic intervention on human
cancer with Akt alteration. (AJTR910005).
Key words: The serine/threonine protein kinase B, PKB, Akt, growth factor receptor, tyrosine kinases,
physiological activity regulation, stability, mammalian target of rapamycin complexes, mTORCs, Pin1, caspase,
DEPTOR, PP2A, pleckstrin homology domain, PH domain, PHLPPs, PHLDAs, hot shock protein
Full Text PDF
Address all correspondence to:
Yong Liao, PhD
Department of Experimental Therapeutics
The University of Texas M. D. Anderson Cancer Center
1515 Holcombe Blvd., TX 77030
USA;
Tel: 713-792-6567
E-mail: yongliao@mdanderson.org;
Mien-Chie Hung, PhD,
Department of Molecular & Cellular Oncology
The University of Texas M.D. Anderson Cancer Center
1515 Holcombe Blvd.
TX 77030, USA;
Tel: 713-792-3668
E-mail: mhung@mdanderson.org.
Review Article
Physiological regulation of Akt activity and stability
Yong Liao, Mien-Chie Hung
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515
Holcombe Blvd., TX 77030, USA; Department of Molecular & Cellular Oncology, The University of Texas M.D.
Anderson Cancer Center, 1515 Holcombe Blvd., TX 77030, USA; and Center for Molecular Medicine and Graduate
Institute of Cancer Biology, China Medical University and Hospital, Taichung 404, Taiwan
Received November 2, 2009; accepted November 3, 2009; available online January 11, 2010
Abstract: The serine/threonine protein kinase B (PKB, also known as Akt) constitutes an important node in
diverse signaling cascades downstream of growth factor receptor tyrosine kinases. Akt plays an essential role in
cell survival, growth, migration, proliferation, polarity, and metabolism (lipid and glucose); cell cycle progression;
muscle and cardiomyocyte contractility; angiogenesis; and self-renewal of stem cells. Altered Akt activity has been
associated with cancer and other disease conditions, such as diabetes mellitus, neurodegenerative diseases,
and muscle hypotrophy. In the past decade, the upstream signals that lead to Akt activation, the downstream
substrates that exert the effects of Akt, and the secondary binding proteins that regulate Akt activation have been
well documented. Recent reports from our group and others have revealed how the stability of Akt protein is
regulated through phosphorylation on its Thr-Pro motifs. This literature review details findings of those reports
and others relevant to the regulation of Akt activation by its upstream kinases, with a focus on mammalian target
of rapamycin complexes (mTORCs) and inactivation by PHLDA3 and the protein phosphatases PP2A and
pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP). Reports on ubiquitin-dependent
Akt degradation, caspase-dependent cleavage, and the role of molecular chaperone heat shock protein 90
(Hsp90) in the regulation of Akt stability are summarized. The highlight will be on the role of “turn motif”
phosphorylation and an isomerase, Pin1, in the regulation of Akt stability. We also discuss issues related to the
intricate mTORC2-Akt-mTORC1 loop and the contradictory regulation of Akt phosphorylation and stabilization of
Akt by mTORC2. Finally, we offer perspective on potential future directions for investigation, particularly on
translating the knowledge we learned on the regulation of Akt stability into therapeutic intervention on human
cancer with Akt alteration. (AJTR910005).
Key words: The serine/threonine protein kinase B, PKB, Akt, growth factor receptor, tyrosine kinases,
physiological activity regulation, stability, mammalian target of rapamycin complexes, mTORCs, Pin1, caspase,
DEPTOR, PP2A, pleckstrin homology domain, PH domain, PHLPPs, PHLDAs, hot shock protein
Full Text PDF
Address all correspondence to:
Yong Liao, PhD
Department of Experimental Therapeutics
The University of Texas M. D. Anderson Cancer Center
1515 Holcombe Blvd., TX 77030
USA;
Tel: 713-792-6567
E-mail: yongliao@mdanderson.org;
Mien-Chie Hung, PhD,
Department of Molecular & Cellular Oncology
The University of Texas M.D. Anderson Cancer Center
1515 Holcombe Blvd.
TX 77030, USA;
Tel: 713-792-3668
E-mail: mhung@mdanderson.org.
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