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2016 ; 113
(38
): 10571-6
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In B cells, phosphatidylinositol 5-phosphate 4-kinase-? synthesizes PI(4,5)P2 to
impact mTORC2 and Akt signaling
#MMPMID27601656
Bulley SJ
; Droubi A
; Clarke JH
; Anderson KE
; Stephens LR
; Hawkins PT
; Irvine RF
Proc Natl Acad Sci U S A
2016[Sep]; 113
(38
): 10571-6
PMID27601656
show ga
Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are enigmatic lipid kinases
with physiological functions that are incompletely understood, not the least
because genetic deletion and cell transfection have led to contradictory data.
Here, we used the genetic tractability of DT40 cells to create cell lines in
which endogenous PI5P4K? was removed, either stably by genetic deletion or
transiently (within 1 h) by tagging the endogenous protein genomically with the
auxin degron. In both cases, removal impacted Akt phosphorylation, and by leaving
one PI5P4K? allele present but mutating it to be kinase-dead or have PI4P
5-kinase activity, we show that all of the effects on Akt phosphorylation were
dependent on the ability of PI5P4K? to synthesize phosphatidylinositol
(4,5)-bisphosphate [PI(4,5)P2] rather than to remove PI5P. Although stable
removal of PI5P4K? resulted in a pronounced decrease in Akt phosphorylation at
Thr308 and Ser473, in part because of reduced plasma membrane PIP3, its acute
removal led to an increase in Akt phosphorylation only at Ser473. This process
invokes activation primarily of mammalian target of rapamycin complex 2 (mTORC2),
which was confirmed by increased phosphorylation of other mTORC2 substrates.
These findings establish PI5P4K? as a kinase that synthesizes a physiologically
relevant pool of PI(4,5)P2 and as a regulator of mTORC2, and show a phenomenon
similar to the "butterfly effect" described for phosphatidylinositol 3-kinase I?
[Hart JR, et al. (2015) Proc Natl Acad Sci USA 112(4):1131-1136], whereby through
apparently the same underlying mechanism, the removal of a protein's activity
from a cell can have widely divergent effects depending on the time course of
that removal.
|Animals
[MESH]
|B-Lymphocytes/enzymology
[MESH]
|Cell Line
[MESH]
|Chickens/genetics
[MESH]
|Humans
[MESH]
|Mechanistic Target of Rapamycin Complex 2/genetics/*metabolism
[MESH]