PMID- 10409742
OWN - NLM
STAT- MEDLINE
DCOM- 19990819
LR  - 20190701
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 19
IP  - 8
DP  - 1999 Aug
TI  - Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK
      localization.
PG  - 5523-34
AB  - Genetic screens for modifiers of activated Ras phenotypes have identified a novel
      protein, kinase suppressor of Ras (KSR), which shares significant sequence
      homology with Raf family protein kinases. Studies using Drosophila melanogaster
      and Caenorhabditis elegans predict that KSR positively regulates Ras signaling;
      however, the function of mammalian KSR is not well understood. We show here that 
      two predicted kinase-dead mutants of KSR retain the ability to complement ksr-1
      loss-of-function alleles in C. elegans, suggesting that KSR may have
      physiological, kinase-independent functions. Furthermore, we observe that murine 
      KSR forms a multimolecular signaling complex in human embryonic kidney 293T cells
      composed of HSP90, HSP70, HSP68, p50(CDC37), MEK1, MEK2, 14-3-3, and several
      other, unidentified proteins. Treatment of cells with geldanamycin, an inhibitor 
      of HSP90, decreases the half-life of KSR, suggesting that HSPs may serve to
      stabilize KSR. Both nematode and mammalian KSRs are capable of binding to MEKs,
      and three-point mutants of KSR, corresponding to C. elegans loss-of-function
      alleles, are specifically compromised in MEK binding. KSR did not alter MEK
      activity or activation. However, KSR-MEK binding shifts the apparent molecular
      mass of MEK from 44 to >700 kDa, and this results in the appearance of MEK in
      membrane-associated fractions. Together, these results suggest that KSR may act
      as a scaffolding protein for the Ras-mitogen-activated protein kinase pathway.
FAU - Stewart, S
AU  - Stewart S
AD  - Department of Biological Chemistry, University of Michigan Medical School, Ann
      Arbor, Michigan 48109-0606, USA.
FAU - Sundaram, M
AU  - Sundaram M
FAU - Zhang, Y
AU  - Zhang Y
FAU - Lee, J
AU  - Lee J
FAU - Han, M
AU  - Han M
FAU - Guan, K L
AU  - Guan KL
LA  - eng
GR  - R01 GM051586/GM/NIGMS NIH HHS/United States
GR  - T32 CA009676/CA/NCI NIH HHS/United States
GR  - 5T32 CA09676/CA/NCI NIH HHS/United States
GR  - GM51586/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (14-3-3 Proteins)
RN  - 0 (Benzoquinones)
RN  - 0 (CDC37 protein, human)
RN  - 0 (Caenorhabditis elegans Proteins)
RN  - 0 (Cdc37 protein, mouse)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Drosophila Proteins)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Helminth Proteins)
RN  - 0 (Lactams, Macrocyclic)
RN  - 0 (Macromolecular Substances)
RN  - 0 (Molecular Chaperones)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Quinones)
RN  - 0 (Transcription Factors)
RN  - 0 (ets-Domain Protein Elk-1)
RN  - 0 (par-5 protein, C elegans)
RN  - EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.- (KSR-1 protein kinase)
RN  - EC 2.7.1.- (MAP2K2 protein, human)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinase 1)
RN  - EC 2.7.11.25 (MAP3K1 protein, human)
RN  - EC 2.7.11.25 (Map3k1 protein, mouse)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 2)
RN  - EC 2.7.12.2 (MAP2K1 protein, human)
RN  - EC 2.7.12.2 (Map2k1 protein, mouse)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 2.7.12.2 (mek-1 protein, C elegans)
RN  - EC 3.6.1.- (Chaperonins)
RN  - Z3K3VJ16KU (geldanamycin)
SB  - IM
MH  - 14-3-3 Proteins
MH  - Animals
MH  - Benzoquinones
MH  - Caenorhabditis elegans/physiology
MH  - *Caenorhabditis elegans Proteins
MH  - Cell Cycle Proteins/metabolism
MH  - Cell Line
MH  - Chaperonins
MH  - *DNA-Binding Proteins
MH  - *Drosophila Proteins
MH  - Genetic Complementation Test
MH  - Heat-Shock Proteins/metabolism
MH  - Helminth Proteins/physiology
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Lactams, Macrocyclic
MH  - *MAP Kinase Kinase 1
MH  - MAP Kinase Kinase 2
MH  - *MAP Kinase Kinase Kinase 1
MH  - Macromolecular Substances
MH  - Mice
MH  - *Mitogen-Activated Protein Kinase Kinases
MH  - Models, Biological
MH  - *Molecular Chaperones
MH  - Molecular Weight
MH  - Multiprotein Complexes
MH  - Phosphorylation
MH  - Protein Kinases/*physiology
MH  - Protein Processing, Post-Translational
MH  - Protein-Serine-Threonine Kinases/*metabolism
MH  - Protein-Tyrosine Kinases/metabolism
MH  - Proteins/metabolism
MH  - Proto-Oncogene Proteins/metabolism
MH  - Quinones/pharmacology
MH  - Signal Transduction/*physiology
MH  - *Transcription Factors
MH  - *Tyrosine 3-Monooxygenase
MH  - ets-Domain Protein Elk-1
PMC - PMC84397
EDAT- 1999/07/20 00:00
MHDA- 1999/07/20 00:01
CRDT- 1999/07/20 00:00
PHST- 1999/07/20 00:00 [pubmed]
PHST- 1999/07/20 00:01 [medline]
PHST- 1999/07/20 00:00 [entrez]
AID - 10.1128/mcb.19.8.5523 [doi]
PST - ppublish
SO  - Mol Cell Biol. 1999 Aug;19(8):5523-34. doi: 10.1128/mcb.19.8.5523.