Dk. Lynch et al., Integrin-linked kinase regulates phosphorylation of serine 473 of protein kinase B by an indirect mechanism, ONCOGENE, 18(56), 1999, pp. 8024-8032
The serine threonine kinase protein kinase B regulates cellular activities
as diverse as glycogen metabolism and apoptosis, Full activation of protein
kinase B requires 3-phosphoinositides and dual phosphorylation on threonin
e-308 and serine-473, CaM-K kinase and 3-phosphoinositide dependent-kinase-
l phosphorylate threonine-308, Integrin-linked kinase reportedly phophoryla
tes serine-473, Consistent,vith this, in a model COS cell system we show th
at expression of wild-type integrin-linked kinase promotes the wortmannin s
ensitive phosphorylation of serine-473 of protein kinase B and its downstre
am substrates, and inhibits C-2-ceramide induced apoptosis, In contrast, in
tegrin-linked kinase mutated in a lysine residue critical for function in p
rotein kinases is inactive in these experiments, and furthermore, acts domi
nantly to block serine-473 phosphorylation induced by ErbB4, However, align
ment of analogous sequences from different species demonstrates that integr
in-linked kinase is not a typical protein kinase and identifies a conserved
serine residue which potentially regulates kinase activity in a phosphoryl
ation dependent manner, Mutation of this serine to aspartate or glutamate,
but not alanine, in combination with the inactivating lysine mutation resto
res integrin-linked kinase dependent phosphorylation of serine-473 of prote
in kinase, These data strongly suggest that integrin-linked kinase does not
possess serine-473 kinase activity but functions as an adaptor to recruit
a serine-473 kinase or phosphatase.