PMID- 22591401
OWN - NLM
STAT- MEDLINE
DCOM- 20130117
LR  - 20211021
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 12
DP  - 2012 May 16
TI  - Impaired degradation followed by enhanced recycling of epidermal growth factor 
      receptor caused by hypo-phosphorylation of tyrosine 1045 in RBE cells.
PG  - 179
LID - 10.1186/1471-2407-12-179 [doi]
AB  - BACKGROUND: Since cholangiocarcinoma has a poor prognosis, several epidermal 
      growth factor receptor (EGFR)-targeted therapies with antibody or small molecule 
      inhibitor treatment have been proposed. However, their effect remains limited. 
      The present study sought to understand the molecular genetic characteristics of 
      cholangiocarcinoma related to EGFR, with emphasis on its degradation and 
      recycling. METHODS: We evaluated EGFR expression and colocalization by 
      immunoblotting and immunofluorescence, cell surface EGFR expression by 
      fluorescence-activated cell sorting (FACS), and EGFR ubiquitination and protein 
      binding by immunoprecipitation in the human cholangiocarcinoma RBE and 
      immortalized cholangiocyte MMNK-1 cell lines. Monensin treatment and Rab11a 
      depletion by siRNA were adopted for inhibition of EGFR recycling. RESULTS: Upon 
      stimulation with EGF, ligand-induced EGFR degradation was impaired and the 
      expression of phospho-tyrosine 1068 and phospho-p44/42 MAPK was sustained in RBE 
      cells as compared with MMNK-1 cells. In RBE cells, the process of EGFR sorting 
      for lysosomal degradation was blocked at the early endosome stage, and 
      non-degradated EGFR was recycled to the cell surface. A disrupted association 
      between EGFR and the E3 ubiquitin ligase c-Cbl, as well as hypo-phosphorylation 
      of EGFR at tyrosine 1045 (Tyr1045), were also observed in RBE cells. CONCLUSION: 
      In RBE cells, up-regulation of EGFR Tyr1045 phosphorylation is a potentially 
      useful molecular alteration in EGFR-targeted therapy. The combination of 
      molecular-targeted therapy determined by the characteristics of individual EGFR 
      phosphorylation events and EGFR recycling inhibition show promise in future 
      treatments of cholangiocarcinoma.
FAU - Gui, Anping
AU  - Gui A
AD  - First Department of Surgery, Shinshu University School of Medicine, Asahi, 
      Matsumoto, Nagano, Japan.
FAU - Kobayashi, Akira
AU  - Kobayashi A
FAU - Motoyama, Hiroaki
AU  - Motoyama H
FAU - Kitazawa, Masato
AU  - Kitazawa M
FAU - Takeoka, Michiko
AU  - Takeoka M
FAU - Miyagawa, Shinichi
AU  - Miyagawa S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120516
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 42HK56048U (Tyrosine)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-cbl)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Bile Duct Neoplasms/genetics/*metabolism
MH  - *Bile Ducts, Intrahepatic
MH  - Cell Line, Tumor
MH  - Cholangiocarcinoma/genetics/*metabolism
MH  - Endosomes/metabolism
MH  - Epidermal Growth Factor/pharmacology
MH  - ErbB Receptors/genetics/*metabolism
MH  - Humans
MH  - Phosphorylation/drug effects
MH  - Protein Binding
MH  - Protein Transport
MH  - Proteolysis/drug effects
MH  - Proto-Oncogene Proteins c-cbl/metabolism
MH  - Signal Transduction/drug effects
MH  - Tyrosine/*metabolism
MH  - Ubiquitination
PMC - PMC3476963
EDAT- 2012/05/18 06:00
MHDA- 2013/01/18 06:00
PMCR- 2012/05/16
CRDT- 2012/05/18 06:00
PHST- 2012/01/23 00:00 [received]
PHST- 2012/04/25 00:00 [accepted]
PHST- 2012/05/18 06:00 [entrez]
PHST- 2012/05/18 06:00 [pubmed]
PHST- 2013/01/18 06:00 [medline]
PHST- 2012/05/16 00:00 [pmc-release]
AID - 1471-2407-12-179 [pii]
AID - 10.1186/1471-2407-12-179 [doi]
PST - epublish
SO  - BMC Cancer. 2012 May 16;12:179. doi: 10.1186/1471-2407-12-179.