Regulation of cytokine-independent survival kinase (CISK) by the Phox homology domain and phosphoinositides.
PKB/Akt and serum and glucocorticoid-regulated kinase (SGK) family kinases are important downstream targets of phosphatidylinositol 3 (PI-3) kinase and have been shown to mediate a variety of cellular processes, including cell growth and survival. Although regulation of Akt can be achieved through several mechanisms, including its phosphoinositide-binding Pleckstrin homology (PH) domain, how SGK kinases are targeted and regulated remains to be elucidated. Unlike Akt, cytokine-independent survival kinase (CISK)/SGK3 contains a Phox homology (PX) domain. PX domains have been implicated in several cellular events involving membrane trafficking. However, their precise function remains unknown. We demonstrate here that the PX domain of CISK interacts with phosphatidylinositol (PtdIns)(3,5)P2, PtdIns(3,4,5)P3, and to a lesser extent PtdIns(4,5)P2. The CISK PX domain is required for targeting CISK to the endosomal compartment. Mutation in the PX domain that abolished its phospholipid binding ability not only disrupted CISK localization, but also resulted in a decrease in CISK activity in vivo. These results suggest that the PX domain regulates CISK localization and function through its direct interaction with phosphoinositides. Therefore, CISK and Akt have evolved to utilize different lipid binding domains to accomplish a similar mechanism of activation in response to PI-3 kinase signaling.
Xu
J
J
Verna and Marrs Mclean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Liu
D
D
Gill
G
G
Songyang
Z
Z
D000595:Amino Acid Sequence; D001665:Binding Sites; D002451:Cell Compartmentation; D011992:Endosomes; D015971:Gene Expression Regulation, Enzymologic; D017874:Immediate-Early Proteins; D008565:Membrane Proteins / Q000302:isolation & purification; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D010716:Phosphatidylinositols / Q000378:metabolism*; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases / Q000302:isolation & purification / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D033921:Vesicular Transport Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases
D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010716:Phosphatidylinositols; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D033921:Vesicular Transport Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases; C093846:early endosome antigen 1; C085072:neutrophil cytosol factor 40K