Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death.
Elevating Akt activation is an obvious clinical strategy to prevent progressive neuronal death in neurological diseases. However, this endeavor has been hindered because of the lack of specific Akt activators. Here, from a cell-based high-throughput chemical genetic screening, we identified a small molecule SC79 that inhibits Akt membrane translocation, but paradoxically activates Akt in the cytosol. SC79 specifically binds to the PH domain of Akt. SC79-bound Akt adopts a conformation favorable for phosphorylation by upstream protein kinases. In a hippocampal neuronal culture system and a mouse model for ischemic stroke, the cytosolic activation of Akt by SC79 is sufficient to recapitulate the primary cellular function of Akt signaling, resulting in augmented neuronal survival. Thus, SC79 is a unique specific Akt activator that may be used to enhance Akt activity in various physiological and pathological conditions.
Department of Pathology, Harvard Medical School, Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA.
Hakryul
H
Jo
Subhanjan
S
Mondal
Dewar
D
Tan
Eiichiro
E
Nagata
Shunya
S
Takizawa
Alok K
AK
Sharma
Qingming
Q
Hou
Kumaran
K
Shanmugasundaram
Amit
A
Prasad
Joe K
JK
Tung
Alexander O
AO
Tejeda
Hengye
H
Man
Alan C
AC
Rigby
Hongbo R
HR
Luo
D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology / Q000378:metabolism*; D016923:Cell Death; D003600:Cytosol / Q000201:enzymology*; D004789:Enzyme Activation; D051379:Mice; D009474:Neurons / Q000473:pathology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D051057:Proto-Oncogene Proteins c-akt