An SH2-domain-containing kinase negatively regulates the phosphatidylinositol-3 kinase pathway

Citation
J. Moniakis et al., An SH2-domain-containing kinase negatively regulates the phosphatidylinositol-3 kinase pathway, GENE DEV, 15(6), 2001, pp. 687-698
Citations number
49
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cell & Developmental Biology
Journal title
GENES & DEVELOPMENT
ISSN journal
0890-9369 → ACNP
Volume
15
Issue
6
Year of publication
2001
Pages
687 - 698
Database
ISI
SICI code
0890-9369(20010315)15:6<687:ASKNRT>2.0.ZU;2-4
Abstract
SHK1 is a novel dual-specificity kinase that contains an SH2 domain in its C-terminal region. We demonstrate that SHK1 is required for proper chemotax is and phagocytosis. Mutant shk1 null cells lack polarity, move very slowly , and exhibit an elevated and temporally extended chemoattractant-mediated activation of the kinase Akt/PKB. GFP fusions of the PH domain of Akt/PKB o r the PH-domain-containing protein CRAC, which become transiently associate d with the plasma membrane after a global stimulation with a chemoattractan t, remain associated with the plasma membrane for an extended period of tim e in shk1 null cells. These results suggest that SHK1 is a negative regulat or of the PI3K (phosphatidylinositol-3 kinase) pathway. Furthermore, when a chemoattractant gradient is applied to a wild-type cell, these PH-domain-c ontaining proteins and the F-actin-binding protein coronin localize to its leading edge, but in an shk1 null cell they become randomly associated with the plasma membrane and cortex, irrespective of the direction of the chemo attractant gradient, suggesting that SHK1 is required for the proper spatio temporal control of F-actin levels in chemotaxing cells. Consistent with su ch functions, SHK1 is localized at the plasma membrane/ cortex, and we show that its SH2 domain is required for this localization and the proper funct ion of SHK1.