Regulation of Ribosomal S6 Kinase 2 by Effectors of the Phosphoinositide 3-Kinase Pathway

Abstract

Ribosomal S6 kinase (S6K1), through phosphorylation of the 40 S ribosomal protein S6 and regulation of 5′-terminal oligopyrimidine tract mRNAs, is an important regulator of cellular translational capacity. S6K1 has also been implicated in regulation of cell size. We have recently identified S6K2, a homolog of S6K1, which phosphorylates S6 in vitroand is regulated by the phosphatidylinositide 3-kinase (PI3-K) and mammalian target of rapamycin pathways in vivo. Here, we characterize S6K2 regulation by PI3-K signaling intermediates and compare its regulation to that of S6K1. We report that S6K2 is activated similarly to S6K1 by the PI3-K effectors phosphoinositide-dependent kinase 1, Cdc42, Rac, and protein kinase Cζ that S6K2 is to by protein kinase Cζ is S6K1. of S6K2 is that of S6K1. We that the S6K2 a in S6K2 regulation the S6K1 by a of by of the S6K2 in an that is to that S6K1 and S6K2 similarly activated by PI3-K effectors that to S6K2 to of its kinase the regulation of the the of Ribosomal S6 kinase (S6K1), through phosphorylation of the 40 S ribosomal protein S6 and regulation of 5′-terminal oligopyrimidine tract mRNAs, is an important regulator of cellular translational capacity. S6K1 has also been implicated in regulation of cell size. We have recently identified S6K2, a homolog of S6K1, which phosphorylates S6 in vitroand is regulated by the phosphatidylinositide 3-kinase (PI3-K) and mammalian target of rapamycin pathways in vivo. Here, we characterize S6K2 regulation by PI3-K signaling intermediates and compare its regulation to that of S6K1. We report that S6K2 is activated similarly to S6K1 by the PI3-K effectors phosphoinositide-dependent kinase 1, Cdc42, Rac, and protein kinase Cζ that S6K2 is to by protein kinase Cζ is S6K1. of S6K2 is that of S6K1. We that the S6K2 a in S6K2 regulation the S6K1 by a of by of the S6K2 in an that is to that S6K1 and S6K2 similarly activated by PI3-K effectors that to S6K2 to of its kinase the regulation of the the of ribosomal S6 kinase 3-kinase mammalian target of rapamycin phosphoinositide-dependent kinase kinase kinase protein kinase ribosomal S6 kinase is a protein kinase that phosphorylates the 40 S ribosomal protein S6 in to S6 phosphorylation of 5′-terminal oligopyrimidine of which ribosomal and S6K1 and the translational of the of S6K1 in and has implicated S6K1 in regulation of cell size. has a of a in that is cell S6K1 through also a S6 phosphorylation and 5′-terminal oligopyrimidine tract to in S6K1, a S6K1 and have recently identified S6K2, a homolog of S6K1 that phosphorylates S6 in S6K2 have been in the S6K1 to S6K1, which the S6K1 in S6K2 is a kinase that of the of S6K1 in the the the of S6K2, S6 and 5′-terminal oligopyrimidine tract of S6K1 and S6K2 the is is of S6K2 of the of a in S6K1. of the in of S6K2 and in and S6K2 the in the kinase and of S6K1 and S6K2 of to S6K2, and phosphorylation is in of phosphorylation identified in S6K1 in in S6K2 that regulation and to of S6K1 and S6K2 in the and to the the of S6K2 also a in S6K1 and S6K2, the and by and S6K1, is that and the kinase by a to the kinase phosphorylation of the is to of S6K1 and the and the kinase (PI3-K) and signaling pathways phosphorylation that to S6K1 the important of pathways in S6K1 S6K1 is by of pathways an of to and and of S6K1 of in S6K1 of an S6K1 is also that S6K1 S6K2 is also to and the S6K1 phosphorylation in S6K2 and PI3-K effectors to S6K1 kinase is a kinase to is regulated by and of in the S6K1 by is a also and and have also been implicated in S6K1 regulation S6K1, is S6K1. We have of and S6K1, the of of signaling has also of the and S6K1 and has that to S6K1 and have recently been to of of S6K1 is of the that is important S6K1, S6K2 is regulated by the PI3-K and signaling pathways We have that a PI3-K S6K2 and that S6K2 is activated by have that S6K2, S6K1, regulated by the PI3-K of the signaling intermediates that S6K2 has been the in and and the of in the S6K1 we to in the regulation of Here, we report that S6K2 is regulated similarly to S6K1 by PI3-K the of S6K2 a the S6K1, is regulated by the PI3-K S6K2 is activated by PI3-K and phosphorylation in S6K1 in S6K2 and S6K1. PI3-K effectors have been implicated in S6K1 the in and S6K2 and S6K1, we to S6K2 is regulated by the PI3-K effectors to S6K1 and to the of S6K2 that PI3-K the and through of and We have that and of of and and of S6K1 of and and in kinase a in regulation of S6K2, of the of S6K1 by in the is that an that of of of and We the that is also the S6K1 of of and the of in to of and protein by by a to kinase in a of a of of and the of and and kinase and and of and and of of and of and in of is in the in the of by which S6K1 is and S6K1 and a that to S6K1 that of is that target S6K1 to a cellular in the of its important to S6K1 and S6K2 is to is that the and We that of is to that to the S6K2 is regulated by We that S6K2 in and of the and target to a the of its to of of and in of is in the and in the of and is regulated by the is activated by and by and phosphorylation by is to S6K1 a S6K1 is of S6K1, and in a signaling S6K2 in we a which in and a S6K1 and S6K2, activated to by of in and activated that S6K2 to regulation by a in of the that by of the is the S6K1 is activated by of of and the is activated by the of in of S6K1 and S6K2 by and activated by and S6K2 is activated by the that S6K1 and S6K2 of of and of and in is in the and in of is by of and of and in is in the and in the of and of and of of and in is in the and in the of S6K2 have important regulation and of S6K1 We to the regulation of the is a of S6K1 and S6K2, we to the of of regulation of the and the and the of the in of the in and and the of S6K1 is is the kinase and is to and S6K2 of the kinase to that the PI3-K in of and of of of in the and of and in and kinase of and to of of in the and to a and to and kinase in and of and of of of in the of in the of and and kinase of that and by activated by is also to by of the S6K2 is of the S6K1 and that the of the a S6K2 S6K1, of the S6K2 by PI3-K is a in the of S6K1 and kinase protein S6K2 is a kinase and and the of to the of and that the of the S6K2 kinase is that of S6K1 that S6K2 kinase is to in by the a S6 is the of the in the that S6K1 and S6K2 and that S6K2 in S6K1 of S6K2 also that S6K2 the of in is important to the signaling pathways and intermediates that S6 kinase to of the recently identified S6K1 S6K2, in the regulation of activated by effectors of the PI3-K Cdc42, Rac, and we that of in the the and of PI3-K is to of S6 PI3-K of S6K1 and S6K2 Here, we that PI3-K effectors to in S6K1 also S6K1 and S6K2 the PI3-K effectors of and is that implicated in S6K2 is that and to the in is to that S6K2, which is Cdc42, Rac, and to and of is that regulation is to of of by of S6K2 report and We that S6K2 the and the the of its We and a in in by in and that and of protein the of of have been signaling and and kinase that S6K2 a the a that to of the PI3-K effectors implicated in S6K2 regulation cellular in we have identified in regulation of is that S6K2 is to by is S6K1. the by which S6K1 is the S6K2 is of to to the a We have that S6K1 the in which is activated by that kinase is a S6K1 we of kinase by of in and report a in the of the in regulation of S6K1 and a to of S6K1 by is to by phosphorylation of and of the of S6K1 in a kinase that of S6K1, which is to by and by the of S6K2 is also to and to PI3-K the of S6K2 to S6K1 to in by the S6K2 activated by and to to S6K1 of S6K1 and S6K2 in the is the the of to the is that the of of S6K2 a in S6K1. that regulation to that of of is the of PI3-K effectors is the the of the is that of the and S6K2 that is in to the We have recently the of the S6K2 in an We report that of the S6K2 by S6K2 is the of the we that regulation of phosphorylation is the the of cell and and We that of and in S6K1 and S6K2 regulated similarly by effectors of the PI3-K we also in and regulation of of S6K2 S6K1, S6K2 to and a of the S6K1 through that S6K1 and S6K2 the that and cellular and to effectors of of S6 ribosomal S6 kinase is a protein kinase that phosphorylates the 40 S ribosomal protein S6 in to S6 phosphorylation of 5′-terminal oligopyrimidine of which ribosomal and S6K1 and the translational of the of S6K1 in and has implicated S6K1 in regulation of cell size. has a of a in that is cell S6K1 through also a S6 phosphorylation and 5′-terminal oligopyrimidine tract to in S6K1, a S6K1 and have recently identified S6K2, a homolog of S6K1 that phosphorylates S6 in S6K2 have been in the S6K1 to S6K1, which the S6K1 in S6K2 is a kinase that of the of S6K1 in the the the of S6K2, S6 and 5′-terminal oligopyrimidine tract of S6K1 and S6K2 the is is of S6K2 of the of a in S6K1. of the in of S6K2 and in S6K1 and S6K2 the in the kinase and of S6K1 and S6K2 of to S6K2, and phosphorylation is in of phosphorylation identified in S6K1 in in S6K2 that regulation and to of S6K1 and S6K2 in the and to the the of S6K2 also a in S6K1. S6K1 and S6K2, the and by and S6K1, is that and the kinase by a to the kinase phosphorylation of the is to of S6K1 and the and the kinase (PI3-K) and signaling pathways phosphorylation that to S6K1 the important of pathways in S6K1 S6K1 is by of pathways an of to and and of S6K1 of in S6K1 of an S6K1 is also that S6K1 S6K2 is also to and the S6K1 phosphorylation in S6K2 and PI3-K effectors to S6K1 kinase is a kinase to is regulated by and of in the S6K1 by is a also and and have also been implicated in S6K1 regulation S6K1, is S6K1. We have of and S6K1, the of of signaling has also of the and S6K1 and has that to S6K1 and have recently been to of of S6K1 is of the that is important S6K1, S6K2 is regulated by the PI3-K and signaling pathways We have that a PI3-K S6K2 and that S6K2 is activated by have that S6K2, S6K1, regulated by the PI3-K of the signaling intermediates that S6K2 has been the in and and the of in the S6K1 we to in the regulation of Here, we report that S6K2 is regulated similarly to S6K1 by PI3-K the of S6K2 a the S6K1, is regulated by the PI3-K S6K2 is activated by PI3-K and phosphorylation in S6K1 in S6K2 and S6K1. 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the of cell and and We that of and in S6K1 and S6K2 regulated similarly by effectors of the PI3-K we also in and regulation of of S6K2 S6K1, S6K2 to and a of the S6K1 through that S6K1 and S6K2 the that and cellular and to effectors of of S6 We of the and of