Activation of the Akt-related cytokine-independent survival kinase requires interaction of its phox domain with endosomal phosphatidylinositol 3-phosphate
Jv. Virbasius et al., Activation of the Akt-related cytokine-independent survival kinase requires interaction of its phox domain with endosomal phosphatidylinositol 3-phosphate, P NAS US, 98(23), 2001, pp. 12908-12913
Citations number
43
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Protein kinases of the Akt and related serum- and glucocorticoid-regulated
kinase (SGK) families are major downstream mediators of phosphatidylinosito
l (Pl) 3-kinase signaling to many cellular processes including metabolic fl
ux, membrane trafficking, and apoptosis. Activation of these kinases is tho
ught to occur at the plasma membrane through their serine and threonine pho
sphorylation by the phosphoinositide-dependent kinase 1 (PDK1) protein kina
se, which interacts with membrane 3'-polyphosphoinositides through its plec
kstrin homology (PH) domain. Here, we demonstrate that the SGK family membe
r cytokine-independent survival kinase (CISK) binds strongly and selectivel
y to the monophosphoinositide Pl(3)P through its phox homology (PX) domain.
Comparing native green fluorescent protein-CISK (EGFP-CISK) to a mutant EG
FP-CISK (Y51A) that displays attenuated binding to Pl(3)P reveals that this
interaction is both necessary and sufficient for its localization to early
endosome antigen (EEA1)positive endosomes. Furthermore, early endosome ass
ociation of expressed epitope-tagged CISK in COS cells directed by binding
of its PX domain to Pl(3)P is required for activation of the CISK protein k
inase by both insulin-like growth factor-1 and epidermal growth factor. Tak
en together, these results reveal a critical role of endosomal Pl(3)P in th
e signal transmission mechanism whereby this survival kinase is activated i
n response to P13-kinase stimulation by growth factors.