期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 22, 页码 7681-7686出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0802896105
关键词
cell proliferation; cell signaling; phosphorylation; surface receptors; tyrosine kinases
资金
- NIAMS NIH HHS [R01 AR051448, AR 051886, P50 AR054086, R01 AR051886, AR 051448] Funding Source: Medline
The mechanism of PDGF-receptor beta (PDGFR beta) activation was explored by analyzing the properties of mutant receptors designed based on the crystal structure of the extracellular region of the related receptor tyrosine kinase KIT/stem cell factor receptor. Here, we demonstrate that PDGF-induced activation of a PDGFR beta mutated in Arg-385 or Glu-390 in D4 (the fourth Ig-like domain of the extracellular region) was compromised, resulting in impairment of a variety of PDGF-induced cellular responses. These experiments demonstrate that homotypic D4 interactions probably mediated by salt bridges between Arg-385 and Glu-390 play an important role in activation of PDGFR beta and all type III receptor tyrosine kinases. We also used a chemical cross-linking agent to covalently cross-link PDGF-stimulated cells to demonstrate that a Glu390Ala mutant of PDGFR beta undergoes typical PDGF-induced receptor dimerization. However, unlike WT PDGFR that is expressed on the surface of ligand-stimulated cells in an active state, PDGF-induced Glu390Ala dimers are inactive. Although the conserved amino acids that are required for mediating D4 homotypic interactions are crucial for PDGFR beta activation, these interactions are dispensable for PDGFR beta dimerization. Moreover, PDGFR beta dimerization is necessary but not sufficient for tyrosine kinase activation.
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