Features of the Catalytic Domains and C Termini of the MAPK Signal-integrating Kinases Mnk1 and Mnk2 Determine Their Differing Activities and Regulatory Properties

The MAPK signal-integrating kinases Mnk1 and Mnk2 are closely related but show marked differences in their basal activities and regulation. Both possess, within their C termini, motifs for binding to MAPKs, although these differ between Mnk1 and Mnk2. Mnk2 shows much higher activity in unstimulated cells than Mnk1, whose activity is greatly increased, e.g. by stimulation of the MEK/ERK pathway. Such increases are sensitive to blockade of that pathway, whereas the activation state of Mnk2 is relatively insensitive to inhibition of upstream signaling. Here we have studied the roles of features in their catalytic domains and C termini in determining their regulatory properties and basal activities. Mnk2 can bind to phosphorylated, active ERK, whereas Mnk1 cannot. Such binding apparently protects ERK against dephosphorylation and inactivation. The high basal activity of Mnk2 and its binding to (phospho)ERK requires features both of the catalytic domain and of the C terminus. For example, within the catalytic region an aspartate in Mnk2 plays a key role. Mutation to alanine inactivates Mnk2. In the C terminus, features within the MAPK-binding motif and to either side of it, including potential phosphorylation sites, affect MAPK binding and activity. The association of Mnks with the scaffold protein eukaryotic initiation factor 4G is negatively modulated by Mnk activity. These data indicate that multiple features determine the activities of the Mnks and thus impact on their ability to phosphorylate physiological substrates such as eukaryotic initiation factor 4E. The MAPK signal-integrating kinases Mnk1 and Mnk2 are closely related but show marked differences in their basal activities and regulation. Both possess, within their C termini, motifs for binding to MAPKs, although these differ between Mnk1 and Mnk2. Mnk2 shows much higher activity in unstimulated cells than Mnk1, whose activity is greatly increased, e.g. by stimulation of the MEK/ERK pathway. Such increases are sensitive to blockade of that pathway, whereas the activation state of Mnk2 is relatively insensitive to inhibition of upstream signaling. Here we have studied the roles of features in their catalytic domains and C termini in determining their regulatory properties and basal activities. Mnk2 can bind to phosphorylated, active ERK, whereas Mnk1 cannot. Such binding apparently protects ERK against dephosphorylation and inactivation. The high basal activity of Mnk2 and its binding to (phospho)ERK requires features both of the catalytic domain and of the C terminus. For example, within the catalytic region an aspartate in Mnk2 plays a key role. Mutation to alanine inactivates Mnk2. In the C terminus, features within the MAPK-binding motif and to either side of it, including potential phosphorylation sites, affect MAPK binding and activity. The association of Mnks with the scaffold protein eukaryotic initiation factor 4G is negatively modulated by Mnk activity. These data indicate that multiple features determine the activities of the Mnks and thus impact on their ability to phosphorylate physiological substrates such as eukaryotic initiation factor 4E. The MAPK 2The abbreviations used are: MAPKsignal-integrating kinaseseIFeukaryotic initiation factorERKextracellular ligand-regulated kinaseHEKhuman embryonic kidneyMAPKmitogen-activated protein kinaseMEKmitogen-activated and extracellular-ligand regulated kinase kinaseMnkMAPK-interacting kinaseRSKribosomal protein S6 kinaseTPAtetradecanoyl phorbol acetateBESN,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acidMKPMAPK phosphatase(P)ERKphosphorylation of ERKKDkinase-dead 2The abbreviations used are: MAPKsignal-integrating kinaseseIFeukaryotic initiation factorERKextracellular ligand-regulated kinaseHEKhuman embryonic kidneyMAPKmitogen-activated protein kinaseMEKmitogen-activated and extracellular-ligand regulated kinase kinaseMnkMAPK-interacting kinaseRSKribosomal protein S6 kinaseTPAtetradecanoyl phorbol acetateBESN,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acidMKPMAPK phosphatase(P)ERKphosphorylation of ERKKDkinase-dead-interacting kinases (Mnks) were first discovered by virtue of their ability to interact with or to be phosphorylated by MAPKs (1Fukunaga R. Hunter T. EMBO J. 1997; 16: 1921-1933Crossref PubMed Scopus (552) Google Scholar, 2Waskiewicz A.J. Flynn A. Proud C.G. Cooper J.A. EMBO J. 1997; 16: 1909-1920Crossref PubMed Scopus (780) Google Scholar). MAPKs phosphorylate two threonine residues within the activation or T-loop of the Mnks leading to their activation. However, the regulatory properties of the various Mnk isoforms differ (3Scheper G.C. Morrice N.A. Proud C.G. PubMed Scopus Google Scholar, G.C. Proud C.G. PubMed Scopus Google Scholar, Flynn A. A.J. Cooper J. Proud C.G. J. PubMed Scopus Google Scholar, A. PubMed Scopus Google Scholar). The for the Mnks is the initiation factor A.J. Flynn A. Proud C.G. Cooper J.A. EMBO J. 1997; 16: 1909-1920Crossref PubMed Scopus (780) Google Scholar). protein the on and and the to the of its for G.C. J. Proud C.G. J. PubMed Scopus Google Scholar, A. PubMed Scopus Google although the of phosphorylation in G.C. Proud C.G. J. PubMed Scopus Google Scholar). in the Mnk have were The were and T. R. R. PubMed Scopus Google Scholar). signal-integrating kinases eukaryotic initiation factor ligand-regulated kinase embryonic protein kinase and extracellular-ligand regulated kinase kinase kinase protein S6 kinase phorbol MAPK phosphorylation of ERK signal-integrating kinases eukaryotic initiation factor ligand-regulated kinase embryonic protein kinase and extracellular-ligand regulated kinase kinase kinase protein S6 kinase phorbol MAPK phosphorylation of ERK are two Mnk in and Mnk1 and Mnk2 Cooper J.A. Scopus Google Scholar). In to two with C termini, as a of G.C. Proud C.G. PubMed Scopus Google Scholar, A. PubMed Scopus Google Scholar, J. R. PubMed Scopus Google Scholar). The of Mnk1 and to as and a MAPK-binding motif that is the isoforms and The to first discovered by and Hunter and by (1Fukunaga R. Hunter T. EMBO J. 1997; 16: 1921-1933Crossref PubMed Scopus (552) Google Scholar, 2Waskiewicz A.J. Flynn A. Proud C.G. Cooper J.A. EMBO J. 1997; 16: 1909-1920Crossref PubMed Scopus (780) Google Scholar). The are Mnk1 and as have in Mnk1 a basal activity but in cells is MAPK-binding motif can bind either ERK or is by that either and its activation is by that ERK or MAPK (3Scheper G.C. Morrice N.A. Proud C.G. PubMed Scopus Google Scholar, G.C. Proud C.G. PubMed Scopus Google Scholar, Flynn A. A.J. Cooper J. Proud C.G. J. PubMed Scopus Google Scholar). In Mnk2 shows a high basal activity in cells that activation of ERK by phorbol the and and on Mnk2 activity (3Scheper G.C. Morrice N.A. Proud C.G. PubMed Scopus Google Scholar, G.C. Proud C.G. PubMed Scopus Google Scholar). Mnk1 a MAPK-binding domain that to bind ERK and but A.J. Flynn A. Proud C.G. Cooper J.A. EMBO J. 1997; 16: 1909-1920Crossref PubMed Scopus (780) Google Scholar). is to bind to ERK, than to and to A.J. Flynn A. Proud C.G. Cooper J.A. EMBO J. 1997; 16: 1909-1920Crossref PubMed Scopus (780) Google Scholar). In is much by ERK than MAPK A.J. Flynn A. Proud C.G. Cooper J.A. EMBO J. 1997; 16: 1909-1920Crossref PubMed Scopus (780) Google Scholar, G.C. Morrice N.A. Proud C.G. PubMed Scopus Google Scholar, J.A. A.J. J. PubMed Scopus Google Scholar). high basal whereas basal activity that is by the ERK and MAPK MAPKs such as ERK a binding interact with their and substrates as and the T. T. PubMed Scopus Google Scholar). is region that bind the MAPK that and MAPKs T. T. PubMed Scopus Google Scholar). The MAPKs phosphorylate in the T-loop of of residues within the T-loop and of protein kinases to their activation PubMed Scopus Google Scholar). the of these residues to the activation of the Mnks by ERK or MAPK A.J. Flynn A. Proud C.G. Cooper J.A. EMBO J. 1997; 16: 1909-1920Crossref PubMed Scopus (780) Google Scholar, G.C. Morrice N.A. Proud C.G. PubMed Scopus Google Scholar). However, are differences in the within the T-loop of Mnk1 and Mnk2. phosphorylate the Mnks bind G.C. Proud C.G. J. PubMed Scopus Google Scholar, R. Hunter T. EMBO J. PubMed Scopus Google Scholar). that phosphorylation of Mnk1 by the phosphorylation of Mnk1 and its with J. A.J. Cooper J.A. J.A. J. PubMed Scopus Google but the of data that the Mnks stimulation (3Scheper G.C. Morrice N.A. Proud C.G. PubMed Scopus Google Scholar). in the that the with the protein the ability of the Mnks to phosphorylate their is to features the marked differences in activity between Mnk1 and and the of their association with we have studied features in the C termini and catalytic domains of Mnk1 and Mnk2 that differences in their activity and and affect their binding to and embryonic cells were in in with were by of the in with cells a of to or to and were used of and cells were with and in of and of and and were for and the to a of to and the for protein of in were and to bind the for an The were with of and in For of cells were in and as The with the and protein and the were with the of the with as were in a of in of and of for The by and the for were by and by phosphorylated and by and by as J. R. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). Mnk1 A.J. Cooper J.A. PubMed Scopus Google Scholar). in Mnk1 or Mnk2 that residues to or to or to or to or to to and the and were the The and were by a in Mnk1 and Mnk2 the with and the to the C were between both by the of of a on protein and for and MAPK were and the against with of of the and the used for of the In and were as J. R. PubMed Scopus Google Scholar). The C of Mnk1 and Mnk2 the in Mnk1 and to the and were used in (3Scheper G.C. Morrice N.A. Proud C.G. PubMed Scopus Google the Mnks in Mnk2 higher basal activity than Mnk1 activity is greatly by cells with that upstream ERK and MAPK Flynn A. A.J. Cooper J. Proud C.G. J. PubMed Scopus Google Scholar). of to the features of Mnk2 that its higher basal activity with Mnk1 in of the high basal activity of the can be in Mnk1 and Mnk2 catalytic are differences between e.g. in the the The differences between Mnk1 and Mnk2 in their C termini MAPK-binding motifs and differ in the MAPK-binding the of between these of Mnk1 and Mnk2 is the that to the motif The MAPK binding in a ability to bind MAPK in to A.J. Flynn A. Proud C.G. Cooper J.A. EMBO J. 1997; 16: 1909-1920Crossref PubMed Scopus (780) Google Scholar). the roles of the C termini in determining the properties of Mnk1 and were in the region between both in The of the region of Mnk2 to the and catalytic domain of Mnk1, and for cells were with Mnk1, Mnk2 or the and cells were for In binding cells were with for cells were with the upstream kinases ERK and by the Mnks with by of the and Mnk activity in as as Mnk2 higher basal activity than Mnk1 the the and catalytic domain of Mnk2 with the C of Mnk1 a much activity than its activity higher than that of that the C of Mnk2 plays a key in the high basal activity of However, the an activity to that of Mnk1, that the C of Mnk2 is by to the high activity that is of Mnk2. that or features the region are is studied in by A.J. Flynn A. Proud C.G. Cooper J.A. EMBO J. 1997; 16: 1909-1920Crossref PubMed Scopus (780) Google that the phosphorylation of ERK its ability to bind to In that a marked of Mnk2 is its ability to bind phosphorylated ERK of the cells although Mnk1, and Mnk2 to ERK, Mnk2 to a to These data that features within the C of Mnk2 are for Mnk2 with although that to ERK A.J. Flynn A. Proud C.G. Cooper J.A. EMBO J. 1997; 16: 1909-1920Crossref PubMed Scopus (780) Google Scholar). However, the of MAPK in the Mnk2 than the with binding than Mnk1, and to than Mnk2. the differences between their MAPK-binding motifs J.A. A.J. J. PubMed Scopus Google Scholar). on ERK binding were the of for and ERK for binding to the of association with MAPK with the or of the region of Mnk2 or the protein that the C of Mnk2 ERK binding than Mnk1 or the activities of Mnk1 and cells to the their for the their cells were with Mnk1 and Mnk2 Mnk1 and cells were for and with for The were and their activities in against a of stimulation of cells with Mnk2 active than Mnk1 of the data a of of that Mnk2 a higher than Mnk1 for and that the of Mnk2 is higher than that of Mnk1 to the of of Mnk2 by a for its and substrates such as the Mnks A.J. Flynn A. Proud C.G. Cooper J.A. EMBO J. 1997; 16: 1909-1920Crossref PubMed Scopus (780) Google Scholar, J. A.J. Cooper J.A. J.A. J. PubMed Scopus Google Scholar). that the binding of to Mnk2 by binding to cells were with Mnk1 or Mnk2 or with the cells were of for and either with for or with by the for of were for the of ERK, as by the with the with in cells with or However, in cells the of higher than in cells or in The of is the in the Mnk2 a of the to dephosphorylation by activation is In cells Mnk1, is against interact with is to and is and the high activity of Mnk2 or of cells with the and Mnk2 both its upstream and protects we to of cells with to and activation of ERK, with Mnk2 of the to the MAPK binding in Mnk1 and Mnk2. of the C termini of Mnk1 and Mnk2 the and of cells were with the for the Mnk were for binding cells were with for The Mnk were an and their ability to bind ERK, or and their T-loop phosphorylation were by with that the of are and be cells were with the Mnk cells were of for cells were with for or and for The Mnk were and kinase were The of shows an of the The shows a to the Mnks as to of the of the Mnk cells were with for to of and for the In the shows a of the Mnks to of the of the and the is an of the for the kinase are the of phosphorylation the The and of the to the of the phosphorylation be that we are that the of Mnk2 is to the of ERK but that the with Mnk2 to the of ERK in its phosphorylated, to the T-loop a in the of data for the Mnk that the differences between the C termini of Mnk1 and Mnk2 their activities and that features in the catalytic domain are an of residues within the T-loop of the catalytic domain of protein kinases is for their activation. is for the MAPKs phosphorylate two residues in that region A.J. Flynn A. Proud C.G. Cooper J.A. EMBO J. 1997; 16: 1909-1920Crossref PubMed Scopus (780) Google Scholar, G.C. Morrice N.A. Proud C.G. PubMed Scopus Google these residues to residues that be (1Fukunaga R. Hunter T. EMBO J. 1997; 16: 1921-1933Crossref PubMed Scopus (552) Google Scholar, G.C. Morrice N.A. Proud C.G. PubMed Scopus Google Scholar). of the of the catalytic domains of Mnk1 and Mnk2 that in Mnk1, residues in the by an aspartate in negatively aspartate or residues phosphorylated or that a in the higher activity of Mnk2. For example, the of a negatively be for the of the to Mnk2 be whereas Mnk1 phosphorylation to be in the catalytic domain of Mnk1 and Mnk2 were The first to in Mnk2. cells were with Mnk1, Mnk2 or the The were to on and the of phosphorylation were by as a of the in activity of the Mnk of Mnk1 phosphorylation these of Mnk2 the phosphorylation of the to a than In Mnk2 in the activities of Mnk2 or the were of cells that in with in the activity either basal or plays a in the basal or activity of Mnk2. aspartate is for the activity of the catalytic domain of that an Mnk1 an aspartate in higher activity. two of Mnk1 were Mnk1 by an and Mnk1 a by an and C is by that of Mnk2 of the to have activity as with Mnk1, in Mnk1 a of we first Mnk1 or Mnk1 in were The Mnk were and by and the were and with by The were by of the for Mnk1 and Mnk1 that is the that is a of is in a for MAPK phosphorylation is by a we a for we a of the T-loop have to alanine to to an of the However, although have activity to the protein e.g. 2Waskiewicz A.J. Flynn A. Proud C.G. Cooper J.A. EMBO J. 1997; 16: 1909-1920Crossref PubMed Scopus (780) Google and G.C. Proud C.G. PubMed Scopus Google such have activity. to we in the motifs of Mnk1 and Mnk2 for in the were of activity. is as the aspartate plays a in the the for the in the that is phosphorylated but by protein although as is to be a However, of be to the activities of the Mnk1 and their to bind in Mnk1 higher activity than Mnk1, but than for Mnk2. Mnk1 activity in to the thus higher than the activity of the that the high activity of Mnk2 be by the properties by its C and by a in the T-loop of Mnk1 its ability to bind phosphorylated ERK The T-loop and to a of binding to that to be a for phosphorylation in Mnk1, we a the the activity of Mnk1, in to the for the affect of by a that phosphorylation of in Mnk1 is for its activity. we a an is in to aspartate but a in its activity to that of as the basal and activities of the and Mnk1 were with the activity both unstimulated and The of an in is apparently to of the in Mnk1 to be The the data in show that the activities of Mnk1 and Mnk2 are by differences in their C termini but by a within their catalytic the MAPK the of Mnks to to MAPK binding in Mnk1 and Mnk2 are their C termini, but Mnk1 and Mnk2 of motif In Mnk1 the whereas in Mnk2 the is data show that the to an in Mnk2 greatly ERK binding to a the phosphorylation of the T-loop J. R. PubMed Scopus Google Scholar). Mnk2 activity both in and in G.C. Proud C.G. PubMed Scopus Google Scholar). The in Mnk1 Mnk1 ERK and MAPK binding the of the differences between the MAPK binding of Mnk1 and we an Mnk1 the MAPK-binding motif of Mnk2 and for Mnk2 Mnk1 ERK binding with Mnk1 to a MAPK binding is with the that the motif is for ERK Mnk2 binding to MAPK to Mnk2. The that Mnk2 to bind in Mnk2 that the or residues are in determining ability to bind be a Mnk1 bind to phosphorylated ERK features of Mnk2 with the to binding to phosphorylation in the activation T-loop that the of Mnk1 of phosphorylation to Mnk1 The in Mnk2 a in T-loop to the of to bind to and In both Mnk1 and the of T-loop with the of these to bind the upstream kinases The that the of Mnk2 bind to to for the high activity of Mnk2 and its to blockade of the MEK/ERK and MAPK In the that Mnk1 than Mnk1 to to stimulation or inhibition of upstream signaling. with the data in Mnk1 higher basal activity than Mnk1, although its activity apparently activity of cells with and whereas Mnk1 by the of these two and whereas the activity of Mnk2 by the Mnk2 bind the of these studied a In the activity of Mnk2 than that of The that in the MAPK-binding motif of Mnk2 both binding and Mnk2 sensitive to inhibition of upstream that the of Mnk2 to such inhibition is a of its ability to bind the binding of Mnk2 to both to active ERK to phosphorylate Mnk2 and dephosphorylation and inactivation. is the data in although the activity of Mnk1 and of the the activity of Mnk1 can bind is to upstream of to the MAPK-binding association between ERK and its substrates can be regulated by phosphorylation residues the domain J. PubMed Scopus Google Scholar). that two residues in and are to the MAPK-binding are phosphorylated in stimulation (3Scheper G.C. Morrice N.A. Proud C.G. PubMed Scopus Google Scholar). These in the is to Mnk1 and Mnk2 Mnk1 a but is by is phosphorylated in Mnk1 in Mnk1 or Mnk1 were The protein with by and the were by as In with on Mnk1 A.J. Cooper J.A. PubMed Scopus Google a of were to phosphorylation within the the the Mnk1 that in Mnk1 is phosphorylated as is in Mnk2 (3Scheper G.C. Morrice N.A. Proud C.G. PubMed Scopus Google but to a and be in the and of to the data that is phosphorylated in is as is in the is in the binding to upstream MAPKs, were to negatively or as or or by In Mnk1, the of by an alanine its binding to ERK and However, in the of by alanine on binding to ERK or that phosphorylation negatively ERK association in Mnk1 but in although is phosphorylated in Mnk2 J. R. PubMed Scopus Google Scholar). features in the C of Mnk2 its binding to ERK of the of by can binding to ERK and in Mnk1 to a or to the to an Mnk1 binding to ERK and as the C and that the of the residues is to their and to of For the ERK and binding in that ERK binding than a on in Mnk2 is phosphorylated in (3Scheper G.C. Morrice N.A. Proud C.G. PubMed Scopus Google apparently in Mnk1, the of phosphorylation in ERK were in Mnk2. Mnk2 both ERK and the ERK but in or its phosphorylation be for its binding to However, is by we can to the MAPK-binding with ERK or in to negatively ERK binding J. PubMed Scopus Google Scholar). In to is in a for phosphorylation by MAPK is by a in were phosphorylated, Mnk2 to be to bind in that is phosphorylated in Mnk2 (3Scheper G.C. Morrice N.A. Proud C.G. PubMed Scopus Google but that a in binding to ERK, to a Mnk2 and Mnk2 or to a negatively Mnk2 and Mnk2 were Mnk2 or Mnk2 ERK binding to the of by aspartate the binding to ERK However, Mnk2 the binding to ERK as Mnk2. a negatively with ERK the in is phosphorylated, in Mnk2 to be (3Scheper G.C. Morrice N.A. Proud C.G. PubMed Scopus Google and Mnk2 can bind the protein cannot. for residues that MAPK binding in to the between the two residues are in is a in whereas is an alanine in Mnk1 are by residues in Mnk1, the is to an and ERK The Mnk2 to bind either ERK or MAPK shows the of in Mnk2 for binding to residues in the in the ERK binding of the J. PubMed Scopus Google and as in T. T. J. PubMed Scopus Google have to be for their with their MAPK these data that features that to the MAPK binding roles in the between Mnk2 and a of the for the differences between Mnk1 and Mnk2 in of MAPK we the region to the MAPK-binding motif for features that be for the ERK the of in the MAPK binding the in Mnk2 is residues is by in Mnk1 is for Mnks and of in Mnk2 by greatly binding to ERK and the with that an is for ERK and The in Mnk1 a in ERK and Mnk1 to bind in Mnk2 to be for binding to However, features be Mnk1 binding to than Mnk2. The of Mnks to the by phosphorylate the Mnks bind the factor G.C. Proud C.G. PubMed Scopus Google Scholar, G.C. Proud C.G. J. PubMed Scopus Google Scholar, R. Hunter T. EMBO J. PubMed Scopus Google Scholar, A.J. Cooper J.A. PubMed Scopus Google Scholar). of the an of phosphorylation in studied the binding to of Mnk1 and Mnk2. Mnk1 to than Mnk2 In of the that the of the Mnks (3Scheper G.C. Morrice N.A. Proud C.G. PubMed Scopus Google and that Mnk2 is much active than Mnk1 basal we binding to higher Mnk kinase activity. we first to the binding of to of the in Mnk1 and Mnk2 to than the the of of Mnk2 the of binding is to that for Mnk1 binding of the in the the of the as as its activity. an we the of the Mnk PubMed Scopus Google Scholar, J. EMBO J. PubMed Scopus Google potential of cells with the Mnk the binding of Mnk1 to the in binding to a by the in the these data that is an between Mnk activity and with protein kinases that of MAPKs, such as the is the and of the The data features that for the activities and regulatory of Mnk1 and their binding to ERK and and the of their binding to Mnk1 shows much basal activity than and the high basal activity of the is to inhibition of the MAPK and ERK the data stimulation of cells with to Mnk1, much activity than Mnk2. the in activity is of to the features in Mnk2 that for high basal activity and for its to inhibition of upstream Mnk1 and Mnk2 a region but show differences in their C These MAPK-binding motifs but a of differences A.J. Flynn A. Proud C.G. Cooper J.A. EMBO J. 1997; 16: 1909-1920Crossref PubMed Scopus (780) Google Scholar). the roles of the C termini in determining the properties of Mnk1 and we of Mnk1 with the C of Mnk2 and the C of Mnk2 with that of Mnk1 a with much activity than the to a with activity to Mnk2. that features of both the C and the catalytic domain are for the high activity of Mnk2. The T-loop of protein kinases a key in their and the of residues that are phosphorylated by the upstream ERK and that a in the T-loop of the catalytic domain of is for its higher activity. Mutation of to in Mnk2 to its inactivation. to a in Mnk1 and of in Mnk1 to to an in its activity. However, the activity of Mnk1 than that of that features are the of the T-loop by in the catalytic domain of Mnk1 and its region for that of Mnk2 a protein that activity to Mnk2 of in the of on protein is that on the of the data indicate that the high basal activity of Mnk2 with to be by a the T-loop and features of its C terminus. of Mnk2 is its ability to bind to The Mnk1 of the C of Mnk2 and the whereas the or have to features in Mnk2 to bind the upstream kinase first ability by the MAPK-binding motif is in Mnk1 and in Mnk2. the of these domains in the binding to the upstream we these motifs between Mnk1 and Mnk2. The MAPK-binding motif in Mnk1 ability to bind MAPK as with Mnk2. the motif binding to ERK and binding to of the by in Mnk2 in a of ability to bind that is for the of a is in the bind that features of Mnk2 are for binding and we to of the of the C termini of Mnk1 and Mnk2 that and features that differ between and be in their binding to The is the that to the MAPK-binding be that the is by in that both are phosphorylated in Mnk2 in (3Scheper G.C. Morrice N.A. Proud C.G. PubMed Scopus Google Scholar). These and were to to a negatively that or to a The these show that of to the binding of Mnk1 to ERK and that phosphorylation negatively the binding of ERK to However, to the ERK and to be phosphorylated within but the that the and show phosphorylation is a of ERK of is to and is to be by a that kinases phosphorylate Mnk1 in In of to or marked on ERK or In to the for Mnk1, its to ERK and of to in Mnk2 the binding of Mnk2 to ERK but binding to indicate a for the phosphorylation of in the the MAPK domain in is to the in and an of the C termini of these residues the MAPK binding The that the to in Mnk2 in the a in the isoforms an between these isoforms is the that but or ERK J. PubMed Scopus Google Scholar). The region the ERK in the is with differences between the The differences between Mnk2 and Mnk2 in their binding to ERK the of these of the However, the of the are features to the MAPK binding in Mnk1 and Mnk2. The differences be for the of Mnk1 and Mnk2 to bind in Mnk2 to a in the ability of Mnk2 to bind The association of with ERK is negatively regulated phosphorylation of J. PubMed Scopus Google Scholar). to in Mnk2. The is phosphorylated in Mnk2 in (3Scheper G.C. Morrice N.A. Proud C.G. PubMed Scopus Google Scholar). studied the of these residues for the binding of Mnk2 to of to or that a in the binding of ERK to Mnk2. In of to the association of Mnk2 to ERK or to an aspartate in Mnk1 be in negatively the binding of Mnk1 to In is a between and to a in the and plays a in the of Mnk2 with ERK, its by an alanine ERK The that the ERK their with the ERK and substrates Mnk2 is insensitive to the The binding of a of the to Mnk2 to to the their binding and thus ERK inactivation. the high basal activity of Mnk2 Mnk2 to can to phosphorylate Mnk2 and in an we studied the of The Mnks bind the protein to phosphorylate we the binding of Mnks to is (3Scheper G.C. Morrice N.A. Proud C.G. PubMed Scopus Google Scholar). that the of with the Mnks is regulated by phosphorylation of residues in Mnk its binding by J. A.J. Cooper J.A. J.A. J. PubMed Scopus Google Scholar). The data that the of association with is on the activation of the The of the Mnks bind to than the of cells with the binding of to The that Mnk2 is active than Mnk1 Mnk1 to than Mnk2 for that in association are to Mnk than to an in the of the Mnks The of the binding be of can be phosphorylated by the Mnks are to The that Mnk to to the or of the phosphorylation of for and for the

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