PMID- 11684694
OWN - NLM
STAT- MEDLINE
DCOM- 20020124
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 277
IP  - 1
DP  - 2002 Jan 4
TI  - Phosphorylation of MEK1 by cdk5/p35 down-regulates the mitogen-activated protein 
      kinase pathway.
PG  - 528-34
AB  - Cyclin-dependent protein kinase 5 (cdk5), a member of the cdk family, is active 
      mainly in postmitotic cells and plays important roles in neuronal development and 
      migration, neurite outgrowth, and synaptic transmission. In this study we 
      investigated the relationship between cdk5 activity and regulation of the 
      mitogen-activated protein (MAP) kinase pathway. We report that cdk5 
      phosphorylates the MAP kinase kinase-1 (MEK1) in vivo as well as the 
      Ras-activated MEK1 in vitro. The phosphorylation of MEK1 by cdk5 resulted in 
      inhibition of MEK1 catalytic activity and the phosphorylation of extracellular 
      signal-regulated kinase (ERK) 1/2. In p35 (cdk5 activator) -/- mice, which lack 
      appreciable cdk5 activity, we observed an increase in the phosphorylation of NF-M 
      subunit of neurofilament proteins that correlated with an up-regulation of MEK1 
      and ERK1/2 activity. The activity of a constitutively active MEK1 with threonine 
      286 mutated to alanine (within a TPXK cdk5 phosphorylation motif in the 
      proline-rich domain) was not affected by cdk5 phosphorylation, suggesting that 
      Thr286 might be the cdk5/p35 phosphorylation-dependent regulatory site. These 
      findings support the hypothesis that cdk5 and the MAP kinase pathway cross-talk 
      in the regulation of neuronal functions. Moreover, these data and the recent 
      studies of Harada et al. (Harada, T., Morooka, T., Ogawa, S., and Nishida, E. 
      (2001) Nat. Cell Biol. 3, 453-459) have prompted us to propose a model for 
      feedback down-regulation of the MAP kinase signal cascade by cdk5 inactivation of 
      MEK1.
FAU - Sharma, Pushkar
AU  - Sharma P
AD  - Laboratory of Neurochemistry, NINDS, National Institutes of Health, Bethesda, 
      Maryland 20892, USA.
FAU - Veeranna
AU  - Veeranna
FAU - Sharma, Monica
AU  - Sharma M
FAU - Amin, Niranjana D
AU  - Amin ND
FAU - Sihag, Ram K
AU  - Sihag RK
FAU - Grant, Philip
AU  - Grant P
FAU - Ahn, Natalie
AU  - Ahn N
FAU - Kulkarni, Ashok B
AU  - Kulkarni AB
FAU - Pant, Harish C
AU  - Pant HC
LA  - eng
PT  - Journal Article
DEP - 20011029
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (neuronal Cdk5 activator (p25-p35))
RN  - 2ZD004190S (Threonine)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Animals
MH  - Cerebral Cortex/metabolism
MH  - Down-Regulation
MH  - MAP Kinase Kinase 1
MH  - *MAP Kinase Signaling System
MH  - Mitogen-Activated Protein Kinase Kinases/*metabolism
MH  - Nerve Tissue Proteins/physiology
MH  - PC12 Cells
MH  - Phosphorylation
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Rats
MH  - Threonine/metabolism
EDAT- 2001/10/31 10:00
MHDA- 2002/01/25 10:01
CRDT- 2001/10/31 10:00
PHST- 2001/10/31 10:00 [pubmed]
PHST- 2002/01/25 10:01 [medline]
PHST- 2001/10/31 10:00 [entrez]
AID - S0021-9258(20)88041-7 [pii]
AID - 10.1074/jbc.M109324200 [doi]
PST - ppublish
SO  - J Biol Chem. 2002 Jan 4;277(1):528-34. doi: 10.1074/jbc.M109324200. Epub 2001 Oct 
      29.