Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 1.
The mitogen-activated protein kinase kinase kinase 3 (MEKK3) is a member of the MAP kinase family whose cellular activity is elevated in response to growth factors, oxidative stress, and hyperosmolar conditions. MEKK3 regulates MKK3 and MKK5/6/7. MEKK3 is involved distinctively in the signal pathway for blocking cell proliferation and cell cycle progression, contradictory to the biological responses commonly associated with other members of MEKKs. Based information concerning the substrate specificity of serum- and glucocorticoid-induced kinase 1 (SGK1), R-x-R-x-x-(S/T)-phi, where phi indicates a hydrophobic amino acid, two putative phosphorylation sites (Ser(166) and Ser(337)) were found in MEKK3. It was shown that the recombinant MEKK3 protein and fluorescein-labeled MEKK3 peptides (FITC-(159)epRsRhlSVi(168) and FITC-(330)dpRgRlpSAd(339)) are phosphorylated by SGK1 in vitro. It was also observed that the intrinsic kinase activity of MEKK3 on Ser(189) of MKK3 (equivalent to Ser(207) of MKK6) decreased along with phosphorylation of Ser(166) and Ser(337) in MEKK3 in vitro and in vivo. Therefore, it is suggested that SGK1 inhibits MEKK3-MKK3/6 signal transduction by phosphorylation of MEKK3.
Chun
Jaesun
J
School of Science Education, Chungbuk National University, Chongju, 361-763, Republic of Korea.
Kwon
Taegun
T
Kim
Dae Joong
DJ
Park
Ingun
I
Chung
Guhung
G
Lee
Eun Jeoung
EJ
Hong
Soon Kwang
SK
Chang
Soo-Ik
SI
Kim
Hack Young
HY
Kang
Sang Sun
SS
D000818:Animals; D019556:COS Cells; D017874:Immediate-Early Proteins; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D000099184:Serum-Glucocorticoid Regulated Kinases
D017874:Immediate-Early Proteins; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases