Ke. Anderson et al., TRANSLOCATION OF PDK-1 TO THE PLASMA-MEMBRANE IS IMPORTANT IN ALLOWING PDK-1 TO ACTIVATE PROTEIN-KINASE-B, Current biology, 8(12), 1998, pp. 684-691
Background: Protein kinase B (PKB) is involved in the regulation of ap
optosis, protein synthesis and glycogen metabolism in mammalian cells.
Phosphoinositide-dependent protein kinase (PDK-1) activates PKB in a
manner dependent on phosphatidylinositol 3,4,5-trisphosphate (Ptdlns(3
,4,5)P-3), which is also needed for the translocation of PKB to the pl
asma membrane. It has been proposed that the amount of PKB activated i
s determined exclusively as a result of its translocation, and that a
constitutively active pool of membrane-associated PDK-1 simply phospho
rylates all the PKB made available. Here, we have investigated the eff
ects of membrane localisation of PDK-1 on PKB activation. Results: Ect
opically expressed PDK-1 translocated to the plasma membrane in respon
se to platelet-derived growth factor (PDGF) and translocation was sens
itive to wortmannin, an inhibitor of phosphoinositide 3-kinase. Transl
ocation of PDK-1 also occurred upon its co-expression with constitutiv
ely active phosphoinositide 3-kinase, but not with an inactive form. O
verexpression of PDK-1 enhanced the ability of PDGF to activate PKB. P
DK-1 disrupted in the pleckstrin homology (PH) domain which did not tr
anslocate to the membrane did not increase PKB activity in response to
PDGF, whereas membrane-targeted PDK-1 activated PKB to the extent tha
t it could not be activated further by PDGF. Conclusions: In response
to PDGF, binding of Ptdlns(3,4,5)P-3 and/or Ptdlns(3,4)P-2 to the PH d
omain of PDK-1 causes its translocation to the plasma membrane where i
t co-localises with PKB, significantly contributing to the scale of PK
B activation.