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Elucidation of the Regulatory Mechanism of Akt Activity and Investigation of Therapeutic Agents Focusing on the Pathway

蔵田, 敦夫 筑波大学 DOI:10.15068/0002008135

2023.09.04

概要

PDK1 was originally identified as a protein Ser/Thr kinase that could phosphorylate Akt
at the Thr308 residue in its activation loop [1, 2]. Later studies have shown that PDK1 is
not only an Akt kinase but also a master regulator of a group of protein kinases known as
the AGC (cAMP-dependent, cGMP-dependent, and protein kinase C) family, including
p70 ribosomal protein S6 kinase (S6K), serum- and glucocorticoid-inducible kinases
(SGKs), protein kinase A (PKA), protein kinase C (PKC) isoforms, and p90 ribosomal
protein S6 kinases (RSKs) at the equivalent residues of Thr308 in Akt (T-loop) [3].
Therefore, PDK1 functions as a pivotal molecule for activation of a number of signaling
pathways involved in proliferation and cell survival. Many components involved in the
downstream of PDK1 have been elucidated, though the regulatory mechanism to control
PDK1 activity is still controversial. It has long been thought that auto-phosphorylation at
the Ser241 residue in the activation loop is sufficient for PDK1 activation [4]. Thus,
PDK1 is thought to be constitutively active in resting cells and not further activated by
growth factor stimulation [5]. However, recent reports suggest that PDK1 activity and
stability are regulated by interaction with other proteins [6-11]. For example, PDK1 binds
to heat shock protein 90 (Hsp90), and its binding protects PDK1 from proteasomedependent degradation. PDK1 also binds to 14-3-3 through the residues surrounding the
auto-phosphorylation site Ser241 and its binding decreases PDK1 kinase activity.
Moreover, Src kinase directly phosphorylates PDK1 at Tyr9, Tyr373, and Tyr376 leading
to an increase in PDK1 kinase activity. ...

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List of Publication

1.

Kurata A, Katayama R, Watanabe T, Tsuruo T, Fujita N

TUSC4/NPRL2, a novel PDK1-interacting protein, inhibits PDK1 tyrosine

phosphorylation and its downstream signaling.

Cancer Sci. 2008 Sep;99(9):1827-34.

2.

Kurata A, Tachibana Y, Takahashi T, Horiba N

Novel AXL-specific inhibitor ameliorates kidney dysfunction through the inhibition of

epithelial-to-mesenchymal transition of renal tubular cells.

PLoS One. 2020 Apr 23;15(4): e0232055.

62

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