PMID- 10597270
OWN - NLM
STAT- MEDLINE
DCOM- 20000106
LR  - 20091119
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 18
IP  - 48
DP  - 1999 Nov 18
TI  - Concentration-dependent positive and negative regulation of a MAP kinase by a MAP
      kinase kinase.
PG  - 6647-57
AB  - There are at least three distinct MAP kinase signaling modules in mammalian
      cells, distinguished by the family of kinases (Erk, SAPK/JNK, or p38) that is
      ultimately activated. Many input signals activate multiple MAP kinase cascades,
      and the mechanisms that control the specificity of signal output are not well
      understood. We show that SEK1/MKK4, a MAP kinase kinase proposed to activate
      SAPK/JNK, is a very potent inhibitor of p54 SAPK beta/JNK3 both in vitro and in
      vivo if present at equimolar or higher ratios. In contrast SEK can activate SAPK 
      when present in substoichiometric amounts, but this activation is slow,
      consistent with the rate-limiting step in activation being the dissociation of an
      inactive SEK:SAPK complex. The N-terminal unique region of SEK is both necessary 
      and partially sufficient for inhibition of SAPK, and is also necessary for
      activation of SAPK by SEK in vitro. We have also used the p38 MAP kinase and its 
      activator MKK6 to examine the regulatory relationships among different kinases
      involved in stress responses. We show using purified kinases that inhibitory
      activity is specific for the combination of SEK and SAPK: SEK can activate but
      not inhibit p38, and MKK6 can activate but not inhibit SAPK beta and p38. These
      results reveal a potential mechanism for regulating stress-activated kinases,
      adding to a growing body of evidence suggesting that MAP kinases are controlled
      by relatively stable interactions with their activators.
FAU - Kieran, M W
AU  - Kieran MW
AD  - Division of Hematology/Oncology, Howard Hughes Medical Institute, Children's
      Hospital, Boston, MA 02115, USA.
FAU - Katz, S
AU  - Katz S
FAU - Vail, B
AU  - Vail B
FAU - Zon, L I
AU  - Zon LI
FAU - Mayer, B J
AU  - Mayer BJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Enzyme Activation
MH  - Humans
MH  - Kinetics
MH  - Mitogen-Activated Protein Kinase Kinases/*metabolism
MH  - Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
MH  - Molecular Sequence Data
MH  - Rats
MH  - Xenopus
EDAT- 1999/12/22 00:00
MHDA- 1999/12/22 00:01
CRDT- 1999/12/22 00:00
PHST- 1999/12/22 00:00 [pubmed]
PHST- 1999/12/22 00:01 [medline]
PHST- 1999/12/22 00:00 [entrez]
AID - 10.1038/sj.onc.1203057 [doi]
PST - ppublish
SO  - Oncogene. 1999 Nov 18;18(48):6647-57. doi: 10.1038/sj.onc.1203057.