PMID- 20208517
OWN - NLM
STAT- MEDLINE
DCOM- 20100519
LR  - 20181201
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Linking)
VI  - 464
IP  - 7289
DP  - 2010 Apr 1
TI  - Spatial control of EGF receptor activation by reversible dimerization on living 
      cells.
PG  - 783-7
LID - 10.1038/nature08827 [doi]
AB  - Epidermal growth factor receptor (EGFR) is a type I receptor tyrosine kinase, the 
      deregulation of which has been implicated in a variety of human carcinomas. EGFR 
      signalling is preceded by receptor dimerization, typically thought to result from 
      a ligand-induced conformational change in the ectodomain that exposes a loop 
      (dimerization arm) required for receptor association. Ligand binding may also 
      trigger allosteric changes in the cytoplasmic domain of the receptor that is 
      crucial for signalling. Despite these insights, ensemble-averaging approaches 
      have not determined the precise mechanism of receptor activation in situ. Using 
      quantum-dot-based optical tracking of single molecules combined with a novel 
      time-dependent diffusivity analysis, here we present the dimerization dynamics of 
      individual EGFRs on living cells. Before ligand addition, EGFRs spontaneously 
      formed finite-lifetime dimers kinetically stabilized by their dimerization arms. 
      The dimers were primed both for ligand binding and for signalling, such that 
      after EGF addition they rapidly showed a very slow diffusivity state that 
      correlated with activation. Although the kinetic stability of unliganded dimers 
      was in principle sufficient for EGF-independent activation, ligand binding was 
      still required for signalling. Interestingly, dimers were enriched in the cell 
      periphery in an actin- and receptor-expression-dependent fashion, resulting in a 
      peripheral enhancement of EGF-induced signalling that may enable polarized 
      responses to growth factors.
FAU - Chung, Inhee
AU  - Chung I
AD  - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
FAU - Akita, Robert
AU  - Akita R
FAU - Vandlen, Richard
AU  - Vandlen R
FAU - Toomre, Derek
AU  - Toomre D
FAU - Schlessinger, Joseph
AU  - Schlessinger J
FAU - Mellman, Ira
AU  - Mellman I
LA  - eng
GR  - R01 AR051886/AR/NIAMS NIH HHS/United States
GR  - P50 AR054086/AR/NIAMS NIH HHS/United States
GR  - R01 AR051448/AR/NIAMS NIH HHS/United States
GR  - P50 AR 054086/AR/NIAMS NIH HHS/United States
GR  - AR 051448/AR/NIAMS NIH HHS/United States
GR  - AR 051886/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100307
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Actins)
RN  - 0 (GRB2 Adaptor Protein)
RN  - 0 (GRB2 protein, human)
RN  - 0 (Ligands)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Actins/metabolism
MH  - Animals
MH  - CHO Cells
MH  - Cell Line, Tumor
MH  - *Cell Polarity
MH  - Cell Survival
MH  - Cricetinae
MH  - Cricetulus
MH  - Diffusion
MH  - Enzyme Activation/drug effects
MH  - Enzyme Stability/drug effects
MH  - Epidermal Growth Factor/metabolism/pharmacology
MH  - ErbB Receptors/agonists/*chemistry/genetics/*metabolism
MH  - GRB2 Adaptor Protein/genetics/metabolism
MH  - Gene Expression Regulation
MH  - Humans
MH  - Kinetics
MH  - Ligands
MH  - *Protein Multimerization/drug effects
MH  - Protein Transport
MH  - Signal Transduction
MH  - Thermodynamics
EDAT- 2010/03/09 06:00
MHDA- 2010/05/21 06:00
CRDT- 2010/03/09 06:00
PHST- 2009/09/21 00:00 [received]
PHST- 2010/01/13 00:00 [accepted]
PHST- 2010/03/09 06:00 [entrez]
PHST- 2010/03/09 06:00 [pubmed]
PHST- 2010/05/21 06:00 [medline]
AID - nature08827 [pii]
AID - 10.1038/nature08827 [doi]
PST - ppublish
SO  - Nature. 2010 Apr 1;464(7289):783-7. doi: 10.1038/nature08827. Epub 2010 Mar 7.