Phosphorylation Out of Order

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Science  27 Feb 2009:
Vol. 323, Issue 5918, pp. 1149
DOI: 10.1126/science.323.5918.1149b

When activated by ligand binding, the fibroblast growth factor receptor (FGFR), like others of its ilk being both a receptor and a tyrosine kinase, undergoes autophosphorylation, which leads not only to an increase in its kinase activity but also to its association with other signaling molecules that then serve as kinase substrates. Lew et al. have explored the mechanism by which five tyrosine residues in FGFR become phospshorylated in an ordered process in which the first phosphorylated tyrosine enhances the kinase activity, the next three provide docking sites for other signaling proteins, and the fifth increases catalytic activity even further. In vitro assays with the complete kinase domain and modified versions thereof showed that the order of phosphorylation depended on the nature of the amino acid sequences surrounding the sites and their location within the three-dimensional structure of the enzyme, and was limited by the rate of transfer of the terminal phosphate group from ATP. The potential biological impact of these carefully ordered events was emphasized by analysis of a mutant form of FGFR1 that has been implicated in the genesis of human glioblastomas. An altered order of modification of the sites led to an increased basal kinase activity of the mutant. The authors note that this and changes in the proper recruitment and regulation of substrate proteins may enable this mutant receptor to cause cell transformation. — LBR

Sci. Signal. 2, ra6 (2009).

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