PMID- 10635327
OWN - NLM
STAT- MEDLINE
DCOM- 20000131
LR  - 20190915
IS  - 1097-2765 (Print)
IS  - 1097-2765 (Linking)
VI  - 4
IP  - 6
DP  - 1999 Dec
TI  - Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of 
      growth factor signaling by c-Cbl/Sli-1.
PG  - 1029-40
AB  - Receptor desensitization is accomplished by accelerated endocytosis and 
      degradation of ligand-receptor complexes. An in vitro reconstituted system 
      indicates that Cbl adaptor proteins directly control downregulation of the 
      receptor for the epidermal growth factor (EGFR) by recruiting 
      ubiquitin-activating and -conjugating enzymes. We infer a sequential process 
      initiated by autophosphorylation of EGFR at a previously identified 
      lysosome-targeting motif that subsequently recruits Cbl. This is followed by 
      tyrosine phosphorylation of c-Cbl at a site flanking its RING finger, which 
      enables receptor ubiquitination and degradation. Whereas all three members of the 
      Cbl family can enhance ubiquitination, two oncogenic Cbl variants, whose RING 
      fingers are defective and phosphorylation sites are missing, are unable to 
      desensitize EGFR. Our study identifies Cbl proteins as components of the 
      ubiquitin ligation machinery and implies that they similarly suppress many other 
      signaling pathways.
FAU - Levkowitz, G
AU  - Levkowitz G
AD  - Department of Biological Regulation, Weizmann Institute of Science, Rehovot, 
      Israel.
FAU - Waterman, H
AU  - Waterman H
FAU - Ettenberg, S A
AU  - Ettenberg SA
FAU - Katz, M
AU  - Katz M
FAU - Tsygankov, A Y
AU  - Tsygankov AY
FAU - Alroy, I
AU  - Alroy I
FAU - Lavi, S
AU  - Lavi S
FAU - Iwai, K
AU  - Iwai K
FAU - Reiss, Y
AU  - Reiss Y
FAU - Ciechanover, A
AU  - Ciechanover A
FAU - Lipkowitz, S
AU  - Lipkowitz S
FAU - Yarden, Y
AU  - Yarden Y
LA  - eng
GR  - CA72981/CA/NCI NIH HHS/United States
GR  - CA78499/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  - United States
TA  - Mol Cell
JT  - Molecular cell
JID - 9802571
RN  - 0 (Caenorhabditis elegans Proteins)
RN  - 0 (Helminth Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Sli-1 protein, C elegans)
RN  - 42HK56048U (Tyrosine)
RN  - 62229-50-9 (Epidermal Growth 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 (ErbB Receptors)
RN  - EC 6.- (Ligases)
RN  - EC 6.2.1.45 (Ubiquitin-Activating Enzymes)
SB  - IM
MH  - *Caenorhabditis elegans Proteins
MH  - Cell-Free System
MH  - Enzyme Activation
MH  - Epidermal Growth Factor/*physiology
MH  - ErbB Receptors/*physiology
MH  - Helminth Proteins/*physiology
MH  - Ligases/*physiology
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins/*physiology
MH  - Proto-Oncogene Proteins c-cbl
MH  - *Signal Transduction
MH  - Tyrosine
MH  - Ubiquitin-Activating Enzymes
MH  - Ubiquitin-Protein Ligases
EDAT- 2000/01/15 00:00
MHDA- 2000/01/15 00:01
CRDT- 2000/01/15 00:00
PHST- 2000/01/15 00:00 [pubmed]
PHST- 2000/01/15 00:01 [medline]
PHST- 2000/01/15 00:00 [entrez]
AID - S1097-2765(00)80231-2 [pii]
AID - 10.1016/s1097-2765(00)80231-2 [doi]
PST - ppublish
SO  - Mol Cell. 1999 Dec;4(6):1029-40. doi: 10.1016/s1097-2765(00)80231-2.