Negative and Positive Regulation of MAPK Phosphatase 3 Controls Platelet-derived Growth Factor-induced Erk Activation

Abstract

MAPK phosphatases (MKPs) are dual specificity phosphatases that dephosphorylate and thereby inactivate MAPKs. In the present study, we provide evidence that platelet-derived growth factor BB (PDGF-BB) regulates MKP3 (DUSP6), which is considered to be a phosphatase highly selective for Erk. Intriguingly, we observed that Mek is positively regulated by MKP3, whereas Erk itself is negatively regulated. In addition, we found that activation of PDGF receptor α or β leads to a rapid proteasomal degradation of MKP3 in a manner that requires Mek activation; this feed-forward mechanism found to be for Erk that of MKP3 and of is in MKP3 of this Erk to of MKP3 and a of Erk in the MKP3 by leads to Erk activation and to In MKP3 is of Erk in a rapid feed-forward and a MAPK phosphatases (MKPs) are dual specificity phosphatases that dephosphorylate and thereby inactivate MAPKs. In the present study, we provide evidence that platelet-derived growth factor BB (PDGF-BB) regulates MKP3 (DUSP6), which is considered to be a phosphatase highly selective for Erk. Intriguingly, we observed that Mek is positively regulated by MKP3, whereas Erk itself is negatively regulated. In addition, we found that activation of PDGF receptor α or β leads to a rapid proteasomal degradation of MKP3 in a manner that requires Mek activation; this feed-forward mechanism found to be for Erk that of MKP3 and of is in MKP3 of this Erk to of MKP3 and a of Erk in the MKP3 by leads to Erk activation and to In MKP3 is of Erk in a rapid feed-forward and a growth factor platelet-derived growth PDGF MAPK platelet-derived growth PDGF MAPK and of and and of PDGF is a of or PDGF or and and to and and to receptor or and for the that and the Erk MAPK the the phosphatase and addition, the which and MAPK is and MAPK and and and and Erk to and In the and in to and the Erk by a the and the factor to the the which the of and Erk of Erk in Erk activation of or of MAPK of Erk activation is to the of Erk in Erk activation by growth factor leads to whereas Erk in that Erk activation is for that the of Erk activation a is specificity the phosphatases (MKPs) are dual specificity phosphatases that negatively the of by the and in the activation growth which the and of MAPK or the to MAPK In the present study, we the of in Erk by and and and and and MKP3 by a the to by a of the in Erk a to the to a the of a to in the MKP3 a of of and the a the In the of and in the the MKP3 a to which the be by and and and and and and in or and and in or or to the by the for and or the and for the of and by and by the of and by to which in in by the and in and in the the or and a for and the of are the to the for for in and for to and and In the and a for in by in in the by and to degradation by of by in and PDGF for of the and to by the for to the for the of the for and for and of MKP3 by a of for of by by and for in by a of and by by and in and by and in and by for are to and considered and Erk or and to Erk activation of the a in the which to and and the of Erk by found that the of Erk which In a activation observed of Erk by a and a of In activation of in Erk that of and a to of we the of the be in Mek of and of the of Erk the of and in the of MAPK to the rapid of Erk by a in we by the of the to be to dephosphorylate Erk. the of and by and for and MKP3 rapid degradation in to in and of MKP3 to by a of degradation In activation of a degradation of MKP3 and a of MKP3 by a of MKP3 activation of Erk of of MKP3 and that in the of Erk are to the of MKP3 the MKP3 degradation of the in the of the in the or of the of MKP3 for the and of degradation found the for the of degradation to be for the of MKP3 of of the Erk is Mek and and of a Erk which is the that the MKP3 the a of are regulated by in a of MKP3 PDGF of MKP3 degradation in the of in the of and are in the of of of MKP3 the of proteasomal in MKP3 the of Mek MKP3 and the of MKP3 and and activation of Erk by MKP3 MKP3 in and are the of Erk of the rapid degradation of MKP3 by the we the of to of MKP3 and the of the proteasomal MKP3 that that MKP3 in to we found that the degradation of MKP3 in and in the of proteasomal we observed that to a Erk activation Erk be to of MKP3 and of Erk. is that of phosphatases is we to of the of and and and for a of MKP3 in this to activation of the Erk is for the degradation of MKP3, we the which Mek and Erk and the MKP3 in a in the rapid degradation of MKP3 in and of in the or of we observed that the of MKP3 of in the of and in we found a in MKP3 In we that the is by in a manner Erk the in MKP3 of in the of be by in of the is that thereby for MKP3 degradation in MKP3 in the that a of MKP3 In of this of MKP3 in a by of in the or of is by in and and for the or for the to and by to and to are for of and and in MKP3 and by and MKP3 to and by to MKP3 and in the by by and and to degradation a to of in is of MKP3 a are to the of and to MKP3 of MKP3 of by and to MKP3 in MKP3 phosphatase thereby to be the the of to in the of are the of the in MKP3 we of the MKP3 and and to degradation and the in which degradation and the the the of of MKP3 and in In the of the whereas and the for we the for MKP3 we and to and and the MKP3 In addition, the MKP3 and to and in MKP3, in in to be to MKP3 in Erk we to the to be in of a of MKP3, of this in the of MKP3 we to that of of MKP3 we we to MKP3 this in this the MKP3 we MKP3 or MKP3 in the of in of MKP3 is in a of MKP3 that we to a in for the MKP3 is of or the of this we in and Erk be in and MKP3 Erk In Mek activation leads to of MKP3, which a rapid degradation of in to the the of MKP3 we of found to a of in and a in in of PDGF to activation of Erk is for of the we the of of we the in MKP3 of of and to a we found a in MKP3 to In addition, of Erk the in MKP3 of to Erk activation for the activation of the we for of in the or of and we a for Erk activation in the of we observed the in of for this of the or activation of the mechanism that the Erk the Erk is in a feed-forward mechanism to degradation of MKP3 and in a by the of MKP3 Mek Erk and the of MKP3, we and the Mek and Erk the found that of MKP3 by the of Erk in to the of MKP3 a Erk the of Erk observed that of MKP3 Mek in to of the In MKP3 to Mek Erk activation In addition, of MKP3 proteasomal to a Mek activation of a of Mek by Erk MKP3 Mek and Erk the to a of Erk of MKP3 Erk Mek MKP3 or MKP3 or and Erk and Mek and activation MKP3 by of or Mek and Erk or a Erk activation of MKP3, we observed a in the to in and in a of Erk in is a of and MKP3 or and for in of the is are of the present study, we the by which the Erk MAPK provide evidence that MKP3, a phosphatase in the of Erk in to In MKP3 is and for proteasomal degradation in a of or in MKP3 degradation is for activation of Erk. a is and MKP3 is to and of Erk. the degradation and of MKP3 are activation of the Erk that feed-forward and In by and that Erk activation proteasomal degradation of a feed-forward of MKP3 leads to Erk and the of this for to of of Erk degradation of MKP3, which a rapid in Erk feed-forward the of MKP3, which a Erk of or to a in of the dual specificity phosphatases and this in for and be by the of a that be by a present in In the of by MKP3 whereas in a in MKP3 of which of and of phosphatases and are to dephosphorylate Erk the of are by provide phosphatase that Erk in the of a In addition, a that to be is that the of the be regulated by PDGF observed that a of MKP3 in and we to that of MKP3 in a this for degradation of MKP3, which we a of a In this that of and leads to of the of the MKP3 degradation in In of and by Erk of is and that that of leads to MKP3 degradation and of and In we to the in MKP3 we MKP3 to of the to in to Erk in we found that the MKP3 MKP3 the In in the of we observed a of the of MKP3, that is a of MKP3 which be by in the of we observed MKP3 in In addition, MKP3 by in the and of a proteasomal we to of and which are we a of in MKP3 by be by of by the of present in be that of for MKP3 to of to MKP3 for the of of the MKP3 in be that in a manner a in addition, Erk activation is for which Erk In that Erk is for in to and is to of the Erk that MKP3 a of Mek observed MKP3 MKP3 be to in Erk Erk of or negatively Mek activation by the of MKP3, the of Erk to be observed that the in MKP3 of and a in of Erk the of Erk is of for the growth the in to the in the PDGF of MKP3 in a in Erk in to Mek that a and Erk activation is to we observed to MKP3 that MKP3 to the Erk activation and In Erk MKP3 to in in the of Erk activation MKP3 degradation and in the in Erk of growth factor platelet-derived growth PDGF MAPK platelet-derived growth PDGF MAPK and of and and of PDGF is a of or PDGF or and and to and and to receptor or and for the that and the Erk MAPK the the phosphatase and addition, the which and MAPK is and MAPK and and and and Erk to and In the and in to and the Erk by a the and the factor to the the which the of and Erk of Erk in Erk activation of or of MAPK of Erk activation is to the of Erk in Erk activation by growth factor leads to whereas Erk in that Erk activation is for that the of Erk activation a is specificity the MAPK phosphatases (MKPs) are dual specificity phosphatases that negatively the of by the and in the activation growth which the and of MAPK or the to MAPK In the present study, we the of in Erk by and and and and and MKP3 by a the to by a of the in Erk a to the to a the of a to in the MKP3 a of of and the a the In the of and in the the MKP3 a to which the be by and and and and and and in or and and in or or to the by the for and or the and for the of and by and by the of and by to which in in by the and in and in the the or and a for and the of are the to the for for in and for to and and In the and a for in by in in the by and to degradation by of by in and PDGF for of the and to by the for to the for the of the for and for and of MKP3 by a of for of by by and for in by a of and by by and in and by and in and by for are to and considered by and and and and and MKP3 by a the to by a of the in Erk a to the to a the of a to in the MKP3 a of of and the a the In the of and in the the MKP3 a to which the be by and and and and and and in or and and in or or to the by the for and or the and for the of and by and by the of and by to which in in by the and in and in the the or and a for and the of are the to the for for in and for to and and In the and a for in by in in the by and to degradation by of by in and PDGF for of the and to by the for to the for the of the for and for and of MKP3 by a of for of by by and for in by a of and by by and in and by and in and by for are to and considered and Erk or and to Erk activation of the a in the which to and and the of Erk by found that the of Erk which In a activation observed of Erk by a and a of In activation of in Erk that of and a to of we the of the be in Mek of and of the of Erk the of and in the of MAPK to the rapid of Erk by a in we by the of the to be to dephosphorylate Erk. the of and by and for and MKP3 rapid degradation in to in and of MKP3 to by a of degradation In activation of a degradation of MKP3 and a of MKP3 by a of MKP3 activation of Erk of of MKP3 and that in the of Erk are to the of MKP3 the MKP3 degradation of the in the of the in the or of the of MKP3 for the and of degradation found the for the of degradation to be for the of MKP3 of of the Erk is Mek and and of a Erk which is the that the MKP3 the a of Erk of the rapid degradation of MKP3 by the we the of to of MKP3 and the of the proteasomal MKP3 that that MKP3 in to we found that the degradation of MKP3 in and in the of proteasomal we observed that to a Erk activation Erk be to of MKP3 and of Erk. is that of phosphatases is we to of the of and and and for a of MKP3 in this to activation of the Erk is for the degradation of MKP3, we the which Mek and Erk and the MKP3 in a in the rapid degradation of MKP3 in and of in the or of we observed that the of MKP3 of in the of and in we found a in MKP3 In we that the is by in a manner Erk the in MKP3 of in the of be by in of the is that thereby for MKP3 degradation in MKP3 in the that a of MKP3 In of this of MKP3 in a by of in the or of is by in and and for the or for the to and by to and to are for of and and in MKP3 and by and MKP3 to and by to MKP3 and in the by by and and to degradation a to of in is of MKP3 a are to the of and to MKP3 of MKP3 of by and to MKP3 in MKP3 phosphatase thereby to be the the of to in the of are the of the in MKP3 we of the MKP3 and and to degradation and the in which degradation and the the the of of MKP3 and in In the of the whereas and the for we the for MKP3 we and to and and the MKP3 In addition, the MKP3 and to and in MKP3, in in to be to MKP3 in Erk we to the to be in of a of MKP3, of this in the of MKP3 we to that of of MKP3 we we to MKP3 this in this the MKP3 we MKP3 or MKP3 in the of in of MKP3 is in a of MKP3 that we to a in for the MKP3 is of or the of this we in and Erk be in and MKP3 Erk In Mek activation leads to of MKP3, which a rapid degradation of in to the the of MKP3 we of found to a of in and a in in of PDGF to activation of Erk is for of the we the of of we the in MKP3 of of and to a we found a in MKP3 to In addition, of Erk the in MKP3 of to Erk activation for the activation of the we for of in the or of and we a for Erk activation in the of we observed the in of for this of the or activation of the mechanism that the Erk the Erk is in a feed-forward mechanism to degradation of MKP3 and in a by the of MKP3 Mek Erk and the of MKP3, we and the Mek and Erk the found that of MKP3 by the of Erk in to the of MKP3 a Erk the of Erk observed that of MKP3 Mek in to of the In MKP3 to Mek Erk activation In addition, of MKP3 proteasomal to a Mek activation of a of Mek by Erk MKP3 Mek and Erk the to a of Erk of MKP3 Erk Mek MKP3 or MKP3 or and Erk and Mek and activation MKP3 by of or Mek and Erk or a Erk activation of MKP3, we observed a in the to in and in a of Erk in is a of and MKP3 or and for in of the is are of and Erk or and to Erk activation of the a in the which to and and the of Erk by found that the of Erk which In a activation observed of Erk by a and a of In activation of in Erk that of and a to of we the of the be in Mek of and of the of Erk the of and in the of MAPK to the rapid of Erk by a in we by the of the to be to dephosphorylate Erk. the of and by and for and MKP3 rapid degradation in to in and of MKP3 to by a of degradation In activation of a degradation of MKP3 and a of MKP3 by a of MKP3 activation of Erk of of MKP3 and that in the of Erk are to the of MKP3 the MKP3 degradation of the in the of the in the or of the of MKP3 for the and of degradation found the for the of degradation to be for the of MKP3 of of the Erk is Mek and and of a Erk which is the that the MKP3 the a of Erk of the rapid degradation of MKP3 by the we the of to of MKP3 and the of the proteasomal MKP3 that that MKP3 in to we found that the degradation of MKP3 in and in the of proteasomal we observed that to a Erk activation Erk be to of MKP3 and of Erk. is that of phosphatases is we to of the of and and and for a of MKP3 in this In to activation of the Erk is for the degradation of MKP3, we the which Mek and Erk and the MKP3 in a in the rapid degradation of MKP3 in and of in the or of we observed that the of MKP3 of in the of and in we found a in MKP3 In we that the is by in a manner Erk the in MKP3 of in the of be by in of the is that thereby for MKP3 degradation in MKP3 in the that a of MKP3 In of this of MKP3 in a by of in the or of the in MKP3 we of the MKP3 and and to degradation and the in which degradation and the the the of of MKP3 and in In the of the whereas and the for we the for MKP3 we and to and and the MKP3 In addition, the MKP3 and to and in MKP3, in in to be to MKP3 in Erk we to the to be in of a of MKP3, of this in the of MKP3 we to that of of MKP3 we we to MKP3 this in this the MKP3 we MKP3 or MKP3 in the of in of MKP3 is in a of MKP3 that we to a in for the MKP3 is of or the of this we in and Erk be in and MKP3 Erk In Mek activation leads to of MKP3, which a rapid degradation of in to the the of MKP3 we of found to a of in and a in in of PDGF In to activation of Erk is for of the we the of of we the in MKP3 of of and to a we found a in MKP3 to In addition, of Erk the in MKP3 of to Erk activation for the activation of the we for of in the or of and we a for Erk activation in the of we observed the in of for this of the or activation of the mechanism that the Erk the Erk is in a feed-forward mechanism to degradation of MKP3 and in a by the of MKP3 MKP3 Mek Erk and the of MKP3, we and the Mek and Erk the found that of MKP3 by the of Erk in to the of MKP3 a Erk the of Erk observed that of MKP3 Mek in to of the In MKP3 to Mek Erk activation In addition, of MKP3 proteasomal to a Mek activation of a of Mek by Erk MKP3 Mek and Erk the to a of Erk In Erk activation of MKP3, we observed a in the to in and in a of Erk in the present study, we the by which the Erk MAPK provide evidence that MKP3, a phosphatase in the of Erk in to In MKP3 is and for proteasomal degradation in a of or in MKP3 degradation is for activation of Erk. a is and MKP3 is to and of Erk. the degradation and of MKP3 are activation of the Erk that feed-forward and In by and that Erk activation proteasomal degradation of a feed-forward of MKP3 leads to Erk and the of this for to of or to a in of the dual specificity phosphatases and this in for and be by the of a that be by a present in In the of by MKP3 whereas in a in MKP3 of which of and of phosphatases and are to dephosphorylate Erk the of are by provide phosphatase that Erk in the of a In addition, a that to be is that the of the be regulated by PDGF observed that a of MKP3 in and we to that of MKP3 in a this for degradation of MKP3, which we a of a In this that of and leads to of the of the MKP3 degradation in In of and by Erk of is and that that of leads to MKP3 degradation and of and In we to the in MKP3 we MKP3 to of the to in to Erk in we found that the MKP3 MKP3 the In in the of we observed a of the of MKP3, that is a of MKP3 which be by in the of we observed MKP3 in In addition, MKP3 by in the and of a proteasomal we to of and which are we a of in MKP3 by be by of by the of present in be that of for MKP3 to of to MKP3 for the of of the MKP3 in be that in a manner a in addition, Erk activation is for which Erk In that Erk is for in to and is to of the Erk that MKP3 a of Mek observed MKP3 MKP3 be to in Erk Erk of or negatively Mek activation by the of MKP3, the of Erk to be observed that the in MKP3 of and a in of Erk the of Erk is of for the growth the in to the in the PDGF of MKP3 in a in Erk in to Mek that a and Erk activation is to we observed to MKP3 that MKP3 to the Erk activation and In Erk MKP3 to in in the of Erk activation MKP3 degradation and in the in Erk of In the present study, we the by which the Erk MAPK provide evidence that MKP3, a phosphatase in the of Erk in to In MKP3 is and for proteasomal degradation in a of or in MKP3 degradation is for activation of Erk. a is and MKP3 is to and of Erk. the degradation and of MKP3 are activation of the Erk that feed-forward and In by and that Erk activation proteasomal degradation of a feed-forward of MKP3 leads to Erk and the of this for to of or to a in of the dual specificity phosphatases and this in for and be by the of a that be by a present in In the of by MKP3 whereas in a in MKP3 of which of and of phosphatases and are to dephosphorylate Erk the of are by provide phosphatase that Erk in the of a In addition, a that to be is that the of the be regulated by PDGF observed that a of MKP3 in and we to that of MKP3 in a this for degradation of MKP3, which we a of a In this that of and leads to of the of the MKP3 degradation in In of and by Erk of is and that that of leads to MKP3 degradation and of and In we to the in MKP3 we MKP3 to of the to in to Erk in we found that the MKP3 MKP3 the In in the of we observed a of the of MKP3, that is a of MKP3 which be by in the of we observed MKP3 in In addition, MKP3 by in the and of a proteasomal we to of and which are we a of in MKP3 by be by of by the of present in be that of for MKP3 to of to MKP3 for the of of the MKP3 in be that in a manner a in In addition, Erk activation is for which Erk In that Erk is for in to and is to of the Erk that MKP3 a of Mek observed MKP3 MKP3 be to in Erk Erk of or negatively Mek activation by the of MKP3, the of Erk to be observed that the in MKP3 of and a in of Erk the of Erk is of for the growth the in to the in the PDGF of MKP3 in a in Erk in to Mek that a and Erk activation is to we observed to MKP3 that MKP3 to the Erk activation and In Erk MKP3 to in in the of Erk activation MKP3 degradation and in the in Erk of for and for and and for the MKP3 and