The structural biology of growth factor receptor activation.
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.
Harmer
Nicholas J
NJ
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
Chirgadze
Dima
D
Hyun Kim
Kyung
K
Pellegrini
Luca
L
Blundell
Tom L
TL
D000818:Animals; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006133:Growth Substances / Q000737:chemistry / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D020932:Nerve Growth Factor / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000737:chemistry* / Q000502:physiology*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000378:metabolism; D013002:Somatomedins / Q000378:metabolism
D006133:Growth Substances; D007328:Insulin; D017468:Receptors, Fibroblast Growth Factor; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; D017451:Receptors, Somatomedin; D013002:Somatomedins; D005346:Fibroblast Growth Factors; D017228:Hepatocyte Growth Factor; D020932:Nerve Growth Factor; D019859:Proto-Oncogene Proteins c-met; D011972:Receptor, Insulin