PMID- 10037737
OWN - NLM
STAT- MEDLINE
DCOM- 19990330
LR  - 20190508
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 10
DP  - 1999 Mar 5
TI  - Vascular endothelial growth factor receptor KDR tyrosine kinase activity is
      increased by autophosphorylation of two activation loop tyrosine residues.
PG  - 6453-60
AB  - Vascular endothelial growth factor is an important physiological regulator of
      angiogenesis. The function of this endothelial cell selective growth factor is
      mediated by two homologous tyrosine kinase receptors, fms-like tyrosine kinase 1 
      (Flt-1) and kinase domain receptor (KDR). Although the functional consequence of 
      vascular endothelial growth factor binding to the Flt-1 receptor is not fully
      understood, it is well established that mitogenic signaling is mediated by KDR.
      Upon sequencing several independent cDNA clones spanning the cytoplasmic region
      of human KDR, we identified and confirmed the identity of a functionally required
      valine at position 848 in the ATP binding site, rather than the previously
      reported glutamic acid residue, which corresponds to an inactive tyrosine kinase.
      The cytoplasmic domain of recombinant native KDR, expressed as a glutathione
      S-transferase fusion protein, can undergo autophosphorylation in the presence of 
      ATP. In addition, the kinase activity can be substantially increased by
      autophosphorylation at physiologic ATP concentrations. Mutation analysis
      indicates that both tyrosine residues 1054 and 1059 are required for activation, 
      which is a consequence of an increased affinity for both ATP and the peptide
      substrate and has no effect on kcat, the intrinsic catalytic activity of the
      enzyme. KDR kinase catalyzes phosphotransfer by formation of a ternary complex
      with ATP and the peptide substrate. We demonstrate that tyrosine kinase
      antagonists can preferentially inhibit either the unactivated or activated form
      of the enzyme.
FAU - Kendall, R L
AU  - Kendall RL
AD  - Department of Cancer Research, Merck Research Laboratories, West Point,
      Pennsylvania 19486, USA. ken_thomas@merck.com
FAU - Rutledge, R Z
AU  - Rutledge RZ
FAU - Mao, X
AU  - Mao X
FAU - Tebben, A J
AU  - Tebben AJ
FAU - Hungate, R W
AU  - Hungate RW
FAU - Thomas, K A
AU  - Thomas KA
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA, Complementary)
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (Lymphokines)
RN  - 0 (Receptors, Growth Factor)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
SB  - IM
MH  - DNA, Complementary/analysis/genetics
MH  - Endothelial Growth Factors/*metabolism
MH  - Enzyme Activation
MH  - Humans
MH  - Lymphokines/*metabolism
MH  - Phosphorylation
MH  - Protein Conformation
MH  - Receptor Protein-Tyrosine Kinases/chemistry/genetics/*metabolism
MH  - Receptors, Growth Factor/chemistry/genetics/*metabolism
MH  - Receptors, Vascular Endothelial Growth Factor
MH  - Tyrosine/*metabolism
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
EDAT- 1999/02/26 00:00
MHDA- 1999/02/26 00:01
CRDT- 1999/02/26 00:00
PHST- 1999/02/26 00:00 [pubmed]
PHST- 1999/02/26 00:01 [medline]
PHST- 1999/02/26 00:00 [entrez]
AID - 10.1074/jbc.274.10.6453 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 Mar 5;274(10):6453-60. doi: 10.1074/jbc.274.10.6453.