serine/threonine protein kinase Sgk1; serum/glucocorticoid-regulated kinase 1 (SGK1, SGK)

Function: - protein kinase that plays an important role in cellular stress response - activates certain K⁺ channels, Na⁺ channels, & chloride channels, suggesting an involvement in the regulation of processes such as cell survival, neuronal excitability & renal Na⁺ excretion - sustained high levels & activity may contribute to conditions such as hypertension & diabetic nephropathy - mediates cell survival signals, phosphorylates & negatively regulates pro-apoptotic FOXO3A - phosphorylates NEDD4L, which leads to its inactivation & to the subsequent activation of various channels & transporters such as ENaC, KCNA3/Kv1.3 or EAAT1 - isoform 2 exhibited a greater effect on cell plasma membrane expression of ENaC & Na⁺ transport than isoform 1 - two specific sites, one in the kinase domain (Thr-256) & the other in the C-terminal regulatory region (Ser-422), need to be phosphorylated for its full activation - activated by WNK1, WNK2, WNK3 & WNK4 (putative) - regulated by phosphorylation - phosphoinositide 3-kinase (PI3-kinase) pathway promotes phosphorylation at Ser-422 which in turn increases the phosphorylation of Thr-256 by PDPK1 - ubiquitinated by NEDD4L; which promotes proteasomal degradation - ubiquitinated by SYVN1 at the endoplasmic reticulum which promotes rapid proteasomal degradation & maintains a high turnover rate in resting cells - isoform 2 shows enhanced stability - isoform 2 resistance to proteasomal degradation is mediated by the sequences within the first 120-amino acid - interacts with NEDD4 & NEDD4L Structure: - isoform 2 subcellular localization at the plasma membrane is mediated by the sequences within the first 120 amino acids - belongs to the protein kinase superfamily, AGC Ser/Thr protein kinase family - contains 1 AGC-kinase C-terminal domain - contains 1 protein kinase domain Compartment: - isoform 2: cell membrane - cytoplasm, nucleus, endoplasmic reticulum - nuclear, upon phosphorylation Alternative splicing: - named isoforms=5 - alternative promoter usage Expression: - expressed in most tissues - expression in the pancreas > placenta, kidney & lung - isoform 2 is strongly expressed in brain & pancreas > heart, placenta, lung, liver & skeletal muscle - isoform 1 is induced by serum &/or glucocorticoids - isoform 2 is not induced by glucocorticoids - by excessive extracellular glucose & by TGFB1, in cultured cells

Properties

SIZE: entity length = 431 aa MW = 49 kD COMPARTMENT: cytoplasm cell nucleus endoplasmic reticulum STATE: active state MOTIF: Necessary for localization to the cytoplasm {1-60} Ser phosphorylation site {S74} Ser phosphorylation site {S78} kinase domain SITE: 98-355 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 104-112 ATP-binding site NAME: ATP-binding site SITE: 127-127 nuclear translocation signal {131-141} lysine-rich region {131-141} MOTIF: lysine residue (SEVERAL) aspartate residue {D222} Thr phosphorylation site {T256} AGC-kinase C-terminal {356-431} MOTIF: Ser phosphorylation site {S397} Ser phosphorylation site {S401} Ser phosphorylation site {S422}

Database Correlations

OMIM 602958 UniProt O00141 PFAM correlations Entrez Gene 6446 Kegg hsa:6446 ENZYME 2.7.11.1

References

UniProt :accession O00141