PMID- 20308550
OWN - NLM
STAT- MEDLINE
DCOM- 20100505
LR  - 20211020
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 107
IP  - 14
DP  - 2010 Apr 6
TI  - The phosphatase and tensin homolog regulates epidermal growth factor receptor 
      (EGFR) inhibitor response by targeting EGFR for degradation.
PG  - 6459-64
LID - 10.1073/pnas.0911188107 [doi]
AB  - The phosphatase and tensin homolog (PTEN) is a tumor suppressor that is 
      inactivated in many human cancers. PTEN loss has been associated with resistance 
      to inhibitors of the epidermal growth factor receptor (EGFR), but the molecular 
      basis of this resistance is unclear. It is believed that unopposed 
      phosphatidylinositol-3-kinase (PI3K) activation through multiple receptor 
      tyrosine kinases (RTKs) can relieve PTEN-deficient cancers from their 
      "dependence" on EGFR or any other single RTK for survival. Here we report a 
      distinct resistance mechanism whereby PTEN inactivation specifically raises EGFR 
      activity by impairing the ligand-induced ubiquitylation and degradation of the 
      activated receptor through destabilization of newly formed ubiquitin ligase Cbl 
      complexes. PTEN-associated resistance to EGFR kinase inhibitors is phenocopied by 
      expression of dominant negative Cbl and can be overcome by more complete EGFR 
      kinase inhibition. PTEN inactivation does not confer resistance to inhibitors of 
      the MET or PDGFRA kinase. Our study identifies a critical role for PTEN in EGFR 
      signal termination and suggests that more potent EGFR inhibition should overcome 
      resistance caused by PI3K pathway activation.
FAU - Vivanco, Igor
AU  - Vivanco I
AD  - Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
FAU - Rohle, Daniel
AU  - Rohle D
FAU - Versele, Matthias
AU  - Versele M
FAU - Iwanami, Akio
AU  - Iwanami A
FAU - Kuga, Daisuke
AU  - Kuga D
FAU - Oldrini, Barbara
AU  - Oldrini B
FAU - Tanaka, Kazuhiro
AU  - Tanaka K
FAU - Dang, Julie
AU  - Dang J
FAU - Kubek, Sara
AU  - Kubek S
FAU - Palaskas, Nicolaos
AU  - Palaskas N
FAU - Hsueh, Teli
AU  - Hsueh T
FAU - Evans, Michael
AU  - Evans M
FAU - Mulholland, David
AU  - Mulholland D
FAU - Wolle, Daniel
AU  - Wolle D
FAU - Rajasekaran, Sigrid
AU  - Rajasekaran S
FAU - Rajasekaran, Ayyappan
AU  - Rajasekaran A
FAU - Liau, Linda M
AU  - Liau LM
FAU - Cloughesy, Timothy F
AU  - Cloughesy TF
FAU - Dikic, Ivan
AU  - Dikic I
FAU - Brennan, Cameron
AU  - Brennan C
FAU - Wu, Hong
AU  - Wu H
FAU - Mischel, Paul S
AU  - Mischel PS
FAU - Perera, Timothy
AU  - Perera T
FAU - Mellinghoff, Ingo K
AU  - Mellinghoff IK
LA  - eng
GR  - U54 CA143798/CA/NCI NIH HHS/United States
GR  - U54CA143798-01/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100322
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-cbl)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - EC 3.1.3.67 (Pten protein, mouse)
RN  - EC 6.3.2.- (CBL protein, human)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Cell Line
MH  - Enzyme Activation
MH  - ErbB Receptors/*antagonists & inhibitors/*metabolism
MH  - Humans
MH  - Mice
MH  - Mice, Knockout
MH  - PTEN Phosphohydrolase/deficiency/genetics/*metabolism
MH  - Protein Binding
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins c-cbl/metabolism
MH  - RNA Interference
MH  - Signal Transduction/drug effects
MH  - Ubiquitination
PMC - PMC2851999
COIS- The authors declare no conflict of interest.
EDAT- 2010/03/24 06:00
MHDA- 2010/05/06 06:00
PMCR- 2010/10/06
CRDT- 2010/03/24 06:00
PHST- 2010/03/24 06:00 [entrez]
PHST- 2010/03/24 06:00 [pubmed]
PHST- 2010/05/06 06:00 [medline]
PHST- 2010/10/06 00:00 [pmc-release]
AID - 0911188107 [pii]
AID - 200911188 [pii]
AID - 10.1073/pnas.0911188107 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6459-64. doi: 
      10.1073/pnas.0911188107. Epub 2010 Mar 22.