Rotational Coupling of the Transmembrane and Kinase Domains of the Neu Receptor Tyrosine Kinase

AUTOR(ES)

Bell, Charlotte A.

FONTE

The American Society for Cell Biology

RESUMO

Ligand binding to receptor tyrosine kinases (RTKs) regulates receptor dimerization and activation of the kinase domain. To examine the role of the transmembrane domain in regulation of RTK activation, we have exploited a simplified transmembrane motif, [VVVEVVV]n, previously shown to activate the Neu receptor. Here we demonstrate rotational linkage of the transmembrane domain with the kinase domain, as evidenced by a periodic activation of Neu as the dimerization motif is shifted across the transmembrane domain. These results indicate that activation requires a specific orientation of the kinase domains with respect to each other. Results obtained with platelet-derived growth factor receptor-β suggest that this rotational linkage of the transmembrane domain to the kinase domain may be a general feature of RTKs. These observations suggest that activating mutations in RTK transmembrane and juxtamembrane domains will be limited to those residues that position the kinase domains in an allowed rotational conformation.

Documentos Relacionados

• Structural analysis of p185c-neu and epidermal growth factor receptor tyrosine kinases: oligomerization of kinase domains.
• The HER-2/neu receptor tyrosine kinase gene encodes a secreted autoinhibitor
• Ligand and p185c-neu density govern receptor interactions and tyrosine kinase activation.
• A single autophosphorylation site confers oncogenicity to the Neu/ErbB-2 receptor and enables coupling to the MAP kinase pathway.
• K-sam gene encodes secreted as well as transmembrane receptor tyrosine kinase.