The Na(+)/H(+) exchanger regulatory factor 2 mediates phosphorylation of serum- and glucocorticoid-induced protein kinase 1 by 3-phosphoinositide-dependent protein kinase 1.
The Na(+)/H(+) exchanger regulatory factor 2 (NHERF2/TKA-1/E3KARP) contains two PSD-95/Dlg/ZO-1 (PDZ) domains which interact with the PDZ docking motif (X-(S/T)-X-(V/L)) of proteins to mediate the assembly of transmembrane and cytosolic proteins into functional signal transduction complexes. One of the PDZ domains of NHERF2 interacts specifically with the DSLL, DSFL, and DTRL motifs present at the carboxy-termini of the 2-adrenergic receptor, the platelet-derived growth factor receptor, and the cystic fibrosis transmembrane conductance regulator, respectively. Serum- and glucocorticoid-induced protein kinase 1 (SGK1) also carries a putative PDZ-binding motif (D-S-F-L) at its carboxy tail, implicated in the specific interaction with NHERF2. There is a 3-phosphoinositide-dependent protein kinase 1 (PDK1) interacting fragment (PIF) in the tail of NHERF2. Using pull-down assays and co-transfection experiments, we demonstrated that the DSFL tail of SGK1 interacts with the first PDZ domain of NHERF2 and the PIF of NHERF2 binds to the PIF-binding pocket of PDK1 to form an SGK1-NHERF2-PDK1 complex. Formation of the protein complex promoted the phosphorylation and activation of SGK1 by PDK1. Thus, it was suggested that NHERF2 mediates the activation and phosphorylation of SGK1 by PDK1 through its first PDZ domain and PIF motif, as a novel SGK1 activation mechanism.
Chun
Jaesun
J
School of Science Education, Chungbuk National University, Gaeshin-dong, Heungdok-gu, Chongju 361-763, Republic of Korea.
Kwon
Taegun
T
Lee
Eunjung
E
Suh
Pann-Ghill
PG
Choi
Eui-Ju
EJ
Sun Kang
Sang
S
D064413:3-Phosphoinositide-Dependent Protein Kinases; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000502:physiology*; D017874:Immediate-Early Proteins; D046911:Macromolecular Substances; D008954:Models, Biological; D009687:Nuclear Proteins; D010750:Phosphoproteins; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017923:Sodium-Hydrogen Exchangers; D000099184:Serum-Glucocorticoid Regulated Kinases
D064413:3-Phosphoinositide-Dependent Protein Kinases; D003598:Cytoskeletal Proteins; D017874:Immediate-Early Proteins; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D017923:Sodium-Hydrogen Exchangers; D000099184:Serum-Glucocorticoid Regulated Kinases; C093376:sodium-hydrogen exchanger regulatory factor