Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment

Jauch, Ralf; Cho, Min Kyu; Jäkel, Stefan; Netter, C.; Schreiter, Kay; Aicher, Babette; Zweckstetter, Markus; Jäckle, Herbert; Wahl, Markus C.

doi:10.1038/sj.emboj.7601285

Cited by 72 publications

(88 citation statements)

References 56 publications

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“…Previous work has suggested that Mnk-inducible phosphorylation of eIF4E is important in the control of cap-dependent translation and protein synthesis in other cellular systems (30)(31)(32), and there is evidence that such phosphorylation promotes HSV-1 mRNA translation and replication (33), and cytokine (TNF␣) biosynthesis (28,29). However, it appears that under certain conditions, Mnk kinases exhibit negative effects on protein translation and synthesis (34,35), while there is evidence for a unique Mnk-regulatory mechanism that involves conversion of the activation segment into an autoinhibitory module (36). It is possible that such an auto-inhibitory mechanism may explain the diversity of responses seen in response to Mnk kinases in different systems, but this remains to be directly established in future studies.…”

Section: Discussionmentioning

confidence: 99%

Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses

Joshi

Kaur

Redig

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 99%

Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses

Joshi

Kaur

Redig

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Two unusual features of the catalytic domains of the Mnks are the presence of (i) a DFD rather than the 'canonical' DFG motif in sub-domain VII and (ii) a short insert (EVFTD in Mnk1) between sub-domains VIII and IX [14]. The crystal structure suggested that the phenylalanine residue of the insert (F230 in hMnk1a) prevents the DFD motif from forming the 'DFG/D-in' conformation which allows ATP binding [13;14].…”

Section: Residues In the Catalytic Domain Of Mnk1 Influence Its Activmentioning

confidence: 99%

“…Recent structural studies of the catalytic domains of the Mnks revealed residues which may play a role in determining their properties, including the differences between Mnk1 and Mnk2 [13;14], thereby prompting questions about the role of the specific conserved residues which differ between these domains of Mnk1 and Mnk2. A c c e p t e d M a n u s c r i p t Licenced copy.…”

Section: Introductionmentioning

confidence: 99%

“…1B). Recent determination of the three-dimensional structure of the catalytic domains of Mnk1 and Mnk2 [13;14] indicates that this may cause the Mnks to have a lower ability to bind their substrate ATP than other protein kinases. These studies also revealed features that may be important for the high basal activity of Mnk2a vs. Mnk1a (which may allow Mnk2a more easily to adopt the active conformation; Fig.…”

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confidence: 99%

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The C-terminal domain of Mnk1a plays a dual role in tightly regulating its activity

Goto

Yao

Proud

2009

Biochemical Journal

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The human family of MAP kinase signal-integrating kinases (Mnks) comprises four related proteins derived from two genes by alternative splicing. The Mnk1 gene gives rise to two proteins, Mnk1a and Mnk1b, which possess distinct C-termini and properties.Despite lacking the C-terminal MAP kinase-binding site, Mnk1b shows higher basal activity than Mnk1a. In contrast, the activity of Mnk1a is tightly regulated by signalling through ERK and p38 MAP kinase.We show that the short C-terminus of Mnk1b confers on it a 'default' behaviour of substantial, but unregulated, activity. In contrast, the longer C-terminus of Mnk1a represses the basal activity and T (activation)-loop phosphorylation of this isozyme while allowing both properties to be stimulated by upstream MAP kinase signalling.Two features of the C-terminus of Mnk1a appear to account for this behaviour: the known MAP kinase-binding site and a region (predicted to be -helical) which occludes access to the catalytic domain and the T-loop. The activation of Mnk1a results in a marked conformational change leading to a more 'open' structure. We also identify a conserved phenylalanine in an Mnk-specific insert as playing a key role in governing the ease with which Mnk1a can be phosphorylated.These studies help to identify the features that give rise to the diverse properties of human Mnk isoforms.Keywords: protein kinase; Mnk; ERK; p38 MAP kinase; eIF4E Abbreviations used: eIF, eukaryotic initiation factor; ERK, extracellular ligand-regulated kinase; HEK, human embryonic kidney; hMnk, human Mnk; MAP kinase, mitogen-activated protein kinase; mMnk, mouse Mnk; Mnk, MAP kinase signal-integrating kinase (or MAP kinase-interacting kinase); NES, nuclear export sequence; NLS, nuclear localisation sequence. A c c e p t e d M a n u s c r i p t Licenced copy. Copying is not permitted, except with prior permission and as allowed by law. © 2009 The Authors Journal compilation © 2009 Portland Press Limited IntroductionThe MAP kinase signal-integrating kinases (also termed 'MAP kinase-interacting' kinases; Mnks) were first discovered by virtue of their abilities to be phosphorylated by [1] or to bind to [2] ERK and/or p38 MAP kinase. There are two Mnk genes in mice and humans, Mnk1 and Mnk2. The Mnk proteins that were originally reported (here termed Mnk1a and Mnk2a) each contain, within their C-terminal regions, a motif for binding to MAP kinases (Fig. 1A). Mnk1a binds well to both ERK and p38 MAP kinases ( / ) while Mnk2a binds better to ERK and only weakly to p38 MAP kinases / [2;3]. ERK and p38 MAP kinases phosphorylate two threonine residues in Mnk1/2 which are located in the activation or 'T'-loop. In many protein kinases phosphorylation in this region leads to their activation.Subsequently it was shown that the human Mnk1 and Mnk2 genes each give rise to two mRNAs, and thus to two distinct polypeptides, as a consequence of alternative mRNA splicing [4][5][6][7] (Fig. 1A). In each case, the second form of each polypeptide (Mnk1b or Mnk2b) contains a distinct C-termina...

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“…Phosphorylation of the A-loop can break such interactions and activate a kinase, as seen for Mnk1 [52]. MSK1 disrupts its active conformation by trapping its A-loop in a b-sheet involving the N-terminus and the pre-helix aC segment [53].…”

Section: Keeping Kinases Inactivementioning

confidence: 99%

Proteus in the World of Proteins: Conformational Changes in Protein Kinases

Rabiller

Getlik

Klüter

et al. 2010

Archiv der Pharmazie

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The 512 protein kinases encoded by the human genome are a prime example of nature's ability to create diversity by introducing variations to a highly conserved theme. The activity of each kinase domain is controlled by layers of regulatory mechanisms involving different combinations of post-translational modifications, intramolecular contacts, and intermolecular interactions. Ultimately, they all achieve their effect by favoring particular conformations that promote or prevent the kinase domain from catalyzing protein phosphorylation. The central role of kinases in various diseases has encouraged extensive investigations of their biological function and three-dimensional structures, yielding a more detailed understanding of the mechanisms that regulate protein kinase activity by conformational changes. In the present review, we discuss these regulatory mechanisms and show how conformational changes can be exploited for the design of specific inhibitors that lock protein kinases in inactive conformations. In addition, we highlight recent developments to monitor ligand-induced structural changes in protein kinases and for screening and identifying inhibitors that stabilize enzymatically incompetent kinase conformations.

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Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment

Cited by 72 publications

References 56 publications

Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses

Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses

The C-terminal domain of Mnk1a plays a dual role in tightly regulating its activity

Proteus in the World of Proteins: Conformational Changes in Protein Kinases

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