Chan TO, Armen RS, Yadav S, Shah S, Zhang J, Tiegs BC, Keny N, Blumhof B, Deshpande DA, Rodeck U, Penn RB. A tripartite cooperative mechanism confers resistance of the protein kinase A catalytic subunit to dephosphorylation. J Biol Chem. 2020 Mar 6;295(10):3316-3329. doi: 10.1074/jbc.RA119.010004. Epub 2020 Jan 21. PMID: 31964716; PMCID: PMC7062156.

We dissected the biochemical, biophysical and physiological mechanisms of a dephosphorylation molecular switch in protein kinase A in airway smooth muscle cells.

Chan TO, Zhang J, Tiegs BC, Blumhof B, Yan L, Keny N, Penny M, Li X, Pascal JM, Armen RS, Rodeck U, Penn RB. Akt kinase C-terminal modifications control activation loop dephosphorylation and enhance insulin response. The Biochemical journal. 2015; 471(1):37-51. NIHMSID: NIHMS740877 PubMed [journal]PMID: 26201515 PMCID: PMC4676407

Chan TO, Zhang J, Rodeck U, Pascal JM, Armen RS, Spring M, Dumitru CD, Myers V, Li X, Cheung JY, Feldman AM. Resistance of Akt kinases to dephosphorylation through ATP-dependent conformational plasticity. Proceedings of the National Academy of Sciences of the United States of America. 2011; 108(46):E1120-7. PubMed [journal]PMID: 22031698 PMCID: PMC3219155

My laboratory made the seminal discovery that an inherited Akt2 mutation linked to severe insulin resistance is a constitutive element of a novel ATP-regulated molecular switch that controls Akt phosphatase sensitivity. This paper was featured in a Science Signaling perspective Science Signaling (ref Humphrey and James, 2012). We are unraveling the mechanism and application of this novel molecular switch as a therapeutic target.

Li X, Mikhalkova D, Gao E, Zhang J, Myers V, Zincarelli C, Lei Y, Song J, Koch WJ, Peppel K, Cheung JY, Feldman AM, Chan TO. Myocardial injury after ischemia-reperfusion in mice deficient in Akt2 is associated with increased cardiac macrophage density. American journal of physiology. Heart and circulatory physiology. 2011; 301(5):H1932-40. PubMed [journal]PMID: 21890689 PMCID: PMC3213957

Understanding the roles of Akt2 kinase in animal cardiac heart failure model.

Chan TO, Rodeck U, Chan AM, Kimmelman AC, Rittenhouse SE, Panayotou G, Tsichlis PN. Small GTPases and tyrosine kinases coregulate a molecular switch in the phosphoinositide 3-kinase regulatory subunit. Cancer Cell. 2002; 1(2):181-91. PubMed [journal]PMID: 12086876

I trained in the laboratory of Dr. Phil Tsichlis, where the Akt kinase was originally identified and cloned. We identified a molecular switch used by tyrosine kinases and small GTPases to coordinately regulate cellular PtdIns-3,4,5-P3  production and Akt activation.