PMID- 10393178
OWN - NLM
STAT- MEDLINE
DCOM- 19990831
LR  - 20161124
IS  - 0261-4189 (Print)
IS  - 1460-2075 (Electronic)
IS  - 0261-4189 (Linking)
VI  - 18
IP  - 13
DP  - 1999 Jul 1
TI  - The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and 
      endocytosis, and attenuates macrophage proliferation.
PG  - 3616-28
AB  - Colony-stimulating factor-1 (CSF-1) activation of the CSF-1 receptor (CSF-1R) 
      causes Cbl protooncoprotein tyrosine phosphorylation, Cbl-CSF-1R association and 
      their simultaneous multiubiquitination at the plasma membrane. The CSF-1R is then 
      rapidly internalized and degraded, whereas Cbl is deubiquitinated in the 
      cytoplasm without being degraded. We have used primary macrophages from 
      gene-targeted mice to study the role of Cbl. Cbl-/- macrophages form denser 
      colonies and, at limiting CSF-1 concentrations, proliferate faster than Cbl+/+ 
      macrophages. Their CSF-1Rs fail to exhibit multiubiquitination and a second wave 
      of tyrosine phosphorylation previously suggested to be involved in preparation of 
      the CSF-1-CSF-1R complex for endocytosis. Consistent with this result, Cbl-/- 
      macrophage cell surface CSF-1-CSF-1R complexes are internalized more slowly, yet 
      are still lysosomally degraded, and the CSF-1 utilization by Cbl-/- macrophages 
      is reduced approximately 2-fold. Thus, attenuation of proliferation by Cbl is 
      associated with its positive regulation of the coordinated multiubiquitination 
      and endocytosis of the activated CSF-1R, and a reduction in the time that the 
      CSF-1R signals from the cell surface. The results provide a paradigm for studies 
      of the mechanisms underlying Cbl attenuation of proliferative responses induced 
      by ligation of receptor tyrosine kinases.
FAU - Lee, P S
AU  - Lee PS
AD  - Department of Developmental and Molecular Biology, Albert Einstein College of 
      Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
FAU - Wang, Y
AU  - Wang Y
FAU - Dominguez, M G
AU  - Dominguez MG
FAU - Yeung, Y G
AU  - Yeung YG
FAU - Murphy, M A
AU  - Murphy MA
FAU - Bowtell, D D
AU  - Bowtell DD
FAU - Stanley, E R
AU  - Stanley ER
LA  - eng
GR  - CA 26504/CA/NCI NIH HHS/United States
GR  - CA 32551/CA/NCI 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  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Ubiquitins)
RN  - 42HK56048U (Tyrosine)
RN  - 81627-83-0 (Macrophage Colony-Stimulating Factor)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-cbl)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.7.10.1 (Receptor, Macrophage Colony-Stimulating Factor)
RN  - EC 3.4.- (Peptide Hydrolases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - EC 3.4.99.- (ATP dependent 26S protease)
RN  - EC 3.6.5.2 (ras Proteins)
RN  - EC 6.3.2.- (Cbl protein, mouse)
SB  - IM
MH  - Animals
MH  - Cell Division
MH  - Cell Size
MH  - Cell Survival
MH  - Cell Transformation, Neoplastic
MH  - Down-Regulation/drug effects
MH  - *Endocytosis/drug effects
MH  - Gene Deletion
MH  - Lysosomes/drug effects/metabolism
MH  - Macrophage Colony-Stimulating Factor/pharmacology
MH  - Macrophages/*cytology/drug effects/metabolism/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Peptide Hydrolases/physiology
MH  - Phosphorylation
MH  - *Proteasome Endopeptidase Complex
MH  - Proto-Oncogene Proteins/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-cbl
MH  - Receptor, Macrophage Colony-Stimulating Factor/*metabolism
MH  - Signal Transduction/drug effects
MH  - Tyrosine/metabolism
MH  - *Ubiquitin-Protein Ligases
MH  - Ubiquitins/*metabolism
MH  - ras Proteins/metabolism
PMC - PMC1171440
EDAT- 1999/07/07 00:00
MHDA- 1999/07/07 00:01
CRDT- 1999/07/07 00:00
PHST- 1999/07/07 00:00 [pubmed]
PHST- 1999/07/07 00:01 [medline]
PHST- 1999/07/07 00:00 [entrez]
AID - 10.1093/emboj/18.13.3616 [doi]
PST - ppublish
SO  - EMBO J. 1999 Jul 1;18(13):3616-28. doi: 10.1093/emboj/18.13.3616.