PMID- 16777603
OWN - NLM
STAT- MEDLINE
DCOM- 20060803
LR  - 20220331
IS  - 0092-8674 (Print)
IS  - 0092-8674 (Linking)
VI  - 125
IP  - 6
DP  - 2006 Jun 16
TI  - An allosteric mechanism for activation of the kinase domain of epidermal growth 
      factor receptor.
PG  - 1137-49
AB  - The mechanism by which the epidermal growth factor receptor (EGFR) is activated 
      upon dimerization has eluded definition. We find that the EGFR kinase domain can 
      be activated by increasing its local concentration or by mutating a leucine 
      (L834R) in the activation loop, the phosphorylation of which is not required for 
      activation. This suggests that the kinase domain is intrinsically autoinhibited, 
      and an intermolecular interaction promotes its activation. Using further 
      mutational analysis and crystallography we demonstrate that the autoinhibited 
      conformation of the EGFR kinase domain resembles that of Src and cyclin-dependent 
      kinases (CDKs). EGFR activation results from the formation of an asymmetric dimer 
      in which the C-terminal lobe of one kinase domain plays a role analogous to that 
      of cyclin in activated CDK/cyclin complexes. The CDK/cyclin-like complex formed 
      by two kinase domains thus explains the activation of EGFR-family receptors by 
      homo- or heterodimerization.
FAU - Zhang, Xuewu
AU  - Zhang X
AD  - Department of Molecular and Cell Biology, Howard Hughes Medical Institute, 
      University of California, Berkeley, 94720, USA.
FAU - Gureasko, Jodi
AU  - Gureasko J
FAU - Shen, Kui
AU  - Shen K
FAU - Cole, Philip A
AU  - Cole PA
FAU - Kuriyan, John
AU  - Kuriyan J
LA  - eng
SI  - PDB/2GS2
SI  - PDB/2GS6
SI  - PDB/2GS7
GR  - R01 CA74305/CA/NCI NIH HHS/United States
GR  - R01 CA96504/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Cell
JT  - Cell
JID - 0413066
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
RN  - GMW67QNF9C (Leucine)
SB  - IM
CIN - Cell. 2006 Jun 16;125(6):1029-31. doi: 10.1016/j.cell.2006.05.028. PMID: 16777592
MH  - Allosteric Regulation
MH  - Amino Acid Sequence
MH  - Animals
MH  - Crystallography, X-Ray
MH  - Cyclin-Dependent Kinases/chemistry
MH  - Dimerization
MH  - Enzyme Activation
MH  - ErbB Receptors/chemistry/genetics/*metabolism
MH  - Humans
MH  - Leucine/genetics
MH  - Mice
MH  - *Models, Molecular
MH  - Molecular Sequence Data
MH  - Mutation
MH  - NIH 3T3 Cells
MH  - Phosphorylation
MH  - Protein Conformation
MH  - Protein Structure, Tertiary
MH  - src-Family Kinases/chemistry
EDAT- 2006/06/17 09:00
MHDA- 2006/08/04 09:00
CRDT- 2006/06/17 09:00
PHST- 2006/03/27 00:00 [received]
PHST- 2006/04/24 00:00 [revised]
PHST- 2006/05/02 00:00 [accepted]
PHST- 2006/06/17 09:00 [pubmed]
PHST- 2006/08/04 09:00 [medline]
PHST- 2006/06/17 09:00 [entrez]
AID - S0092-8674(06)00584-8 [pii]
AID - 10.1016/j.cell.2006.05.013 [doi]
PST - ppublish
SO  - Cell. 2006 Jun 16;125(6):1137-49. doi: 10.1016/j.cell.2006.05.013.