PMID- 12646390
OWN - NLM
STAT- MEDLINE
DCOM- 20031204
LR  - 20190901
IS  - 0301-4622 (Print)
IS  - 0301-4622 (Linking)
VI  - 100
IP  - 1-3
DP  - 2003
TI  - The structural biology of growth factor receptor activation.
PG  - 545-53
AB  - Stimulation of cells by growth factors triggers cascades of signalling that 
      result in cellular responses such as growth, differentiation, migration and 
      survival. Many growth factors signal through receptor tyrosine kinases, leading 
      to dimerization, trans-phosphorylation and activation of tyrosine kinases that 
      phosphorylate components further downstream of the signal transduction cascade. 
      Using insulin-like growth factor, nerve growth factor, hepatocyte growth factor 
      and fibroblast growth factor as examples, we show that the globular architecture 
      of the growth factors is essential for receptor binding. We describe how nerve 
      growth factor (NGF) is a symmetrical dimer that binds four storage proteins (two 
      alpha-NGF and two gamma-NGF) to give a symmetrical hetero-hexameric 7SNGF 
      organised around the beta-NGF dimer. It binds the extracellular domains of two 
      receptor molecules in a similar way, so dimerising the receptor. Hepatocyte 
      growth factor/scatter factor (HGF/SF) probably binds its receptor as a dimer 
      stabilised by interactions with heparan sulfate, and fibroblast growth factor 
      (FGF) binds its receptor as a dimer cross-linked by heparan sulfate. 
      Surprisingly, insulin and insulin-like growth factor (IGF) bind in the monomeric 
      form to receptors that are already covalent dimers. We propose that, in general, 
      weak binary interactions between growth factor and individual domains of 
      receptors are enhanced by cooperative interactions with further receptor domains, 
      and sometimes other components like heparan, to give rise to specific 
      multi-protein/domain complexes.
FAU - Harmer, Nicholas J
AU  - Harmer NJ
AD  - Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, 
      Cambridge CB2 1GA, UK.
FAU - Chirgadze, Dima
AU  - Chirgadze D
FAU - Hyun Kim, Kyung
AU  - Hyun Kim K
FAU - Pellegrini, Luca
AU  - Pellegrini L
FAU - Blundell, Tom L
AU  - Blundell TL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - Biophys Chem
JT  - Biophysical chemistry
JID - 0403171
RN  - 0 (Growth Substances)
RN  - 0 (Insulin)
RN  - 0 (Receptors, Fibroblast Growth Factor)
RN  - 0 (Receptors, Growth Factor)
RN  - 0 (Receptors, Nerve Growth Factor)
RN  - 0 (Receptors, Somatomedin)
RN  - 0 (Somatomedins)
RN  - 62031-54-3 (Fibroblast Growth Factors)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - 9061-61-4 (Nerve Growth Factor)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 2.7.10.1 (Receptor, Insulin)
SB  - IM
MH  - Animals
MH  - Fibroblast Growth Factors/metabolism
MH  - Growth Substances/chemistry/metabolism
MH  - Hepatocyte Growth Factor/metabolism
MH  - Humans
MH  - Insulin/metabolism
MH  - Nerve Growth Factor/chemistry/metabolism
MH  - Protein Conformation
MH  - Proto-Oncogene Proteins c-met/metabolism
MH  - Receptor, Insulin/metabolism
MH  - Receptors, Fibroblast Growth Factor/metabolism
MH  - Receptors, Growth Factor/*chemistry/*physiology
MH  - Receptors, Nerve Growth Factor/metabolism
MH  - Receptors, Somatomedin/metabolism
MH  - Somatomedins/metabolism
EDAT- 2003/03/21 04:00
MHDA- 2003/12/05 05:00
CRDT- 2003/03/21 04:00
PHST- 2003/03/21 04:00 [pubmed]
PHST- 2003/12/05 05:00 [medline]
PHST- 2003/03/21 04:00 [entrez]
AID - S0301462202003058 [pii]
AID - 10.1016/s0301-4622(02)00305-8 [doi]
PST - ppublish
SO  - Biophys Chem. 2003;100(1-3):545-53. doi: 10.1016/s0301-4622(02)00305-8.