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Department of Chemistry and Biochemistry and Center for Molecular Genetics, University of California, San Diego, La Jolla,
California 92093-0367
The receptor tyrosine kinase p185c-neu can be
constitutively activated by the transmembrane domain
mutation Val664
Glu, found in the oncogenic mutant
p185neu. This mutation is predicted to allow intermolecular hydrogen bonding and receptor dimerization. Understanding the activation of p185c-neu has assumed
greater relevance with the recent observation that achondroplasia, the most common genetic form of human dwarfism, is caused by a similar transmembrane
domain mutation that activates fibroblast growth factor
receptor (FGFR) 3. We have isolated novel transforming derivatives of p185c-neu using a large pool of degenerate oligonucleotides encoding variants of the transmembrane domain. Several of the transforming isolates identified were unusual in that they lacked a Glu at residue 664, and others were unique in that they contained
multiple Glu residues within the transmembrane domain. The Glu residues in the transforming isolates often exhibited a spacing of seven residues or occurred in
positions likely to represent the helical interface. However, the distinction between the sequences of the
transforming clones and the nontransforming clones
did not suggest clear rules for predicting which specific
sequences would result in receptor activation and transformation. To investigate these requirements further, entirely novel transmembrane sequences were constructed based on tandem repeats of simple heptad sequences. Activation was achieved by transmembrane
sequences such as [VVVEVVA]n or [VVVEVVV]n,
whereas activation was not achieved by a transmembrane domain consisting only of Val residues. In the
context of these transmembrane domains, Glu or Gln
were equally activating, while Lys, Ser, and Asp were not. Using transmembrane domains with two Glu residues, the spacing between these was systematically varied from two to eight residues, with only the heptad
spacing resulting in receptor activation. These results
are discussed in the context of activating mutations in
the transmembrane domain of FGFR3 that are responsible for the human developmental syndromes achondroplasia and acanthosis nigricans with Crouzon Syndrome.
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