The death effector domain-containing DEDD supports S6K1 activity via preventing Cdk1-dependent inhibitory phosphorylation.
Cell cycle regulation and biochemical responses upon nutrients and growth factors are the major regulatory mechanisms for cell sizing in mammals. Recently, we identified that the death effector domain-containing DEDD impedes mitotic progression by inhibiting Cdk1 (cyclin-dependent kinase 1) and thus maintains an increase of cell size during the mitotic phase. Here we found that DEDD also associates with S6 kinase 1 (S6K1), downstream of phosphatidylinositol 3-kinase, and supports its activity by preventing inhibitory phosphorylation of S6K1 brought about by Cdk1 during the mitotic phase. DEDD(-/-) cells showed reduced S6K1 activity, consistently demonstrating decreased levels in activating phosphorylation at the Thr-389 site. In addition, levels of Cdk1-dependent inhibitory phosphorylation at the C terminus of S6K1 were enhanced in DEDD(-/-) cells and tissues. Consequently, as in S6K1(-/-) mice, the insulin mass within pancreatic islets was reduced in DEDD(-/-) mice, resulting in glucose intolerance. These findings suggest a novel cell sizing mechanism achieved by DEDD through the maintenance of S6K1 activity prior to cell division. Our results also suggest that DEDD may harbor important roles in glucose homeostasis and that its deficiency might be involved in the pathogenesis of type 2 diabetes mellitus.
Kurabe
Nobuya
N
Division of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo, Japan.
Arai
Satoko
S
Nishijima
Akemi
A
Kubota
Naoto
N
Suizu
Futoshi
F
Mori
Mayumi
M
Kurokawa
Jun
J
Kondo-Miyazaki
Miki
M
Ide
Tomohiro
T
Murakami
Kouji
K
Miyake
Katsuhisa
K
Ueki
Kohjiro
K
Koga
Hisashi
H
Yatomi
Yutaka
Y
Tashiro
Fumio
F
Noguchi
Masayuki
M
Kadowaki
Takashi
T
Miyazaki
Toru
T
D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D048429:Cell Size; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*
D053418:Death Domain Receptor Signaling Adaptor Proteins; C486432:Dedd protein, mouse; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D016203:CDC2 Protein Kinase