Identification of the NIMA family kinases NEK6/7 as regulators of the p70 ribosomal S6 kinase.
BACKGROUND
The p70 S6 kinase, like several other AGC family kinases, requires for activation the concurrent phosphorylation of a site on its activation loop and a site carboxyterminal to the catalytic domain, situated in a hydrophobic motif site FXXFS/TF/Y, e.g.,Thr412 in p70 S6 kinase (alpha 1). Phosphorylation of the former site is catalyzed by PDK1, whereas the kinase responsible for the phosphorylation of the latter site is not known.


RESULTS
The major protein kinase that is active on the p70 S6 kinase hydrophobic regulatory site, Thr412, was purified from rat liver and identified as the NIMA-related kinases NEK6 and NEK7. Recombinant NEK6 phosphorylates p70 S6 kinase at Thr412 and other sites and activates the p70 S6 kinase in vitro and in vivo, in a manner synergistic with PDK1. Kinase-inactive NEK6 interferes with insulin activation of p70 S6 kinase. The activity of recombinant NEK6 is dependent on its phosphorylation, but NEK6 activity is not regulated by PDK1 and is only modestly responsive to insulin and PI-3 kinase inhibitors.


CONCLUSIONS
NEK6 and probably NEK7 are novel candidate physiologic regulators of the p70 S6 kinase.
Belham
C
C
Diabetes Unit, Medical Services, Massachusetts General Hospital, Boston, MA 02114, USA.
Comb
M J
MJ
Avruch
J
J
D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D008969:Molecular Sequence Data; D000072380:NIMA-Related Kinase 1; D000072379:NIMA-Related Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013912:Threonine / Q000378:metabolism
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D007328:Insulin; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013912:Threonine; D000072380:NIMA-Related Kinase 1; D000072379:NIMA-Related Kinases; C442331:NIMA-related kinase 6; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases