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Regulation of Akt signaling

Maya Kunkel

Appointment Period: 2001-2002 / Grant Year: [17]

Maya KunkelThe serine/threonine kinase Akt is a critical regulator of insulin signaling, cell survival and oncogenesis. This enzyme is the cellular homolog of the viral oncogene v-Akt and its isoforms have been found to be overexpressed in several cancer cell lines. In response to activating signals, Akt is chemically modified by phosphorylation at two distinct sites: a site within its activation loop and a site within the carboxyl-terminal hydrophobic tail. The upstream kinase responsible for phosphorylation of the activation loop site has been identified as the phosophoinositide-dependent protein kinase 1, PDK-1. Since the identification of PDK-1 as the kinase responsible for Akt activation, PDK-1 has been shown to be the upstream kinase involved in phosphorylation at the activation loop site of a number of additional serine/threonine kinases including PKC, PRK, RSK, p70S6-K, SGK and PAK. Recently, our lab demonstrated that PDK-1 further regulates one of these kinases (PKC) by directly binding to its carboxyl-terminus, thereby preventing autophosphorylation at the hydrophobic site until PDK-1 is released. One aspect of my research is to explore whether PDK-1 also regulates other downstream targets through a similar mechanism. Specifically, the interaction that has been observed between PDK-1 and Akt will be examined. A second aim of my research is to examine the mechanisms by which Akt signaling is terminated; the phosphorylation of Akt is critical for its activation and has been well characterized, however, the molecular mechanisms of Akt desensitization and deactivation are only poorly understood. These studies will examine the dephosphorylation of Akt following stimulus treatment, as well as examine potential long-term downregulation of the kinase in response to prolonged stimulation. Using a pharmacological approach, this work will explore the balance within the cell between Akt activation via phosphorylation and deactivation via phosphatase activity in order to elucidate mechanisms by which Akt signaling is regulated and terminated. Identifying pathways that regulate Akt signaling will aid in designing appraoches to modify its activity in cases, such as in certain cancers, where Akt signaling is overly active.

PUBLICATIONS (resulting from this training, and some recent ones)

Kunkel MT, Ni Q, Tsien RY, Zhang J, Newton AC. (2005) Spatio-temporal dynamics of protein kinase B/Akt signaling revealed by a genetically encoded fluorescent reporter. J Biol Chem. 280:5581-7.

Gallegos LL, Kunkel MT, Newton AC. (2006) Targeting protein kinase C activity reporter to discrete intracellular regions reveals spatiotemporal differences in agonist-dependent signaling. J Biol Chem. 281:30947-56.

Kunkel MT, Toker A, Tsien RY, Newton AC. (2007) Calcium-dependent regulation of protein kinase D revealed by a genetically encoded kinase activity reporter. J Biol Chem. 282:6733-42.