PMID- 19650764
OWN - NLM
STAT- MEDLINE
DCOM- 20091013
LR  - 20211203
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 423
IP  - 2
DP  - 2009 Sep 25
TI  - The C-terminal domain of Mnk1a plays a dual role in tightly regulating its 
      activity.
PG  - 279-90
LID - 10.1042/BJ20090228 [doi]
AB  - The human family of MAPK (mitogen-activated protein 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 
      MAPK-binding site, Mnk1b shows higher basal activity than Mnk1a. In contrast, the 
      activity of Mnk1a is tightly regulated by signalling through ERK 
      (extracellular-signal-regulated kinase) and p38 MAPK. 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 isoenzyme while 
      allowing both properties to be stimulated by upstream MAPK signalling. Two 
      features of the C-terminus of Mnk1a appear to account for this behaviour: the 
      known MAPK-binding site and a region (predicted to be alpha-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 identified a conserved phenylalanine residue 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.
FAU - Goto, Susan
AU  - Goto S
AD  - Department of Biochemistry and Molecular Biology and the Diabetes Research Group, 
      University of British Columbia, 2350 Health Sciences Mall, Vancouver, British 
      Columbia, Canada.
FAU - Yao, Zhong
AU  - Yao Z
FAU - Proud, Christopher G
AU  - Proud CG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090925
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Isoenzymes)
RN  - 2ZD004190S (Threonine)
RN  - 47E5O17Y3R (Phenylalanine)
RN  - EC 2.7.1.- (MKNK1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Amino Acid Sequence
MH  - Catalytic Domain/physiology
MH  - Cells, Cultured
MH  - Enzyme Activation/physiology
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/*chemistry/*metabolism/physiology
MH  - Isoenzymes/chemistry/metabolism/physiology
MH  - Models, Biological
MH  - Molecular Sequence Data
MH  - Phenylalanine/metabolism/physiology
MH  - Phosphorylation
MH  - Protein Conformation
MH  - Protein Serine-Threonine Kinases/*chemistry/*metabolism/physiology
MH  - Protein Structure, Tertiary/physiology
MH  - Sequence Homology, Amino Acid
MH  - Structure-Activity Relationship
MH  - Threonine/chemistry/metabolism/physiology
EDAT- 2009/08/05 09:00
MHDA- 2009/10/14 06:00
CRDT- 2009/08/05 09:00
PHST- 2009/08/05 09:00 [entrez]
PHST- 2009/08/05 09:00 [pubmed]
PHST- 2009/10/14 06:00 [medline]
AID - BJ20090228 [pii]
AID - 10.1042/BJ20090228 [doi]
PST - epublish
SO  - Biochem J. 2009 Sep 25;423(2):279-90. doi: 10.1042/BJ20090228.