Skip to main content
Genetics logoLink to Genetics
. 1991 Sep;129(1):191–201. doi: 10.1093/genetics/129.1.191

Interallelic Complementation among Der/Flb Alleles: Implications for the Mechanism of Signal Transduction by Receptor-Tyrosine Kinases

E Raz 1, E D Schejter 1, B Z Shilo 1
PMCID: PMC1204566  PMID: 1936959

Abstract

The large number of available embryonic lethal alleles in the Drosophila EGF receptor homolog (DER)/faint little ball locus allowed us to test the possibility of positive or negative interactions among different DER alleles. These interactions were monitored by examining the embryonic cuticular phenotypes of different heteroallelic combinations. Several positive interactions were identified, while negative interactions were restricted to a single allele. This is the first example of positive interactions within the same cell type among alleles of a receptor tyrosine kinase gene. The basis for these interactions is likely to arise from the mechanism of signal transduction by receptor tyrosine kinases, which involves receptor aggregation. A combination of two different DER mutant proteins defective in temporally distinct stages of the signal transduction process, may thus form a functional heterodimer. The mutation sites in four alleles showing positive interactions were localized. They identify regions within the protein which are likely to be important for these temporally distinct signal transduction processes.

Full Text

The Full Text of this article is available as a PDF (6.5 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aroian R. V., Koga M., Mendel J. E., Ohshima Y., Sternberg P. W. The let-23 gene necessary for Caenorhabditis elegans vulval induction encodes a tyrosine kinase of the EGF receptor subfamily. Nature. 1990 Dec 20;348(6303):693–699. doi: 10.1038/348693a0. [DOI] [PubMed] [Google Scholar]
  2. Aroian R. V., Sternberg P. W. Multiple functions of let-23, a Caenorhabditis elegans receptor tyrosine kinase gene required for vulval induction. Genetics. 1991 Jun;128(2):251–267. doi: 10.1093/genetics/128.2.251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baker N. E., Rubin G. M. Effect on eye development of dominant mutations in Drosophila homologue of the EGF receptor. Nature. 1989 Jul 13;340(6229):150–153. doi: 10.1038/340150a0. [DOI] [PubMed] [Google Scholar]
  4. Banerjee U., Zipursky S. L. The role of cell-cell interaction in the development of the Drosophila visual system. Neuron. 1990 Feb;4(2):177–187. doi: 10.1016/0896-6273(90)90093-u. [DOI] [PubMed] [Google Scholar]
  5. Bargmann C. I., Hung M. C., Weinberg R. A. The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature. 1986 Jan 16;319(6050):226–230. doi: 10.1038/319226a0. [DOI] [PubMed] [Google Scholar]
  6. Clifford R. J., Schüpbach T. Coordinately and differentially mutable activities of torpedo, the Drosophila melanogaster homolog of the vertebrate EGF receptor gene. Genetics. 1989 Dec;123(4):771–787. doi: 10.1093/genetics/123.4.771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fincham V. J., Wyke J. A. Localization of temperature-sensitive transformation mutations and back mutations in the Rous sarcoma virus src gene. J Virol. 1986 May;58(2):694–699. doi: 10.1128/jvi.58.2.694-699.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Greenwald I., Seydoux G. Analysis of gain-of-function mutations of the lin-12 gene of Caenorhabditis elegans. Nature. 1990 Jul 12;346(6280):197–199. doi: 10.1038/346197a0. [DOI] [PubMed] [Google Scholar]
  9. Greenwald I. lin-12, a nematode homeotic gene, is homologous to a set of mammalian proteins that includes epidermal growth factor. Cell. 1985 Dec;43(3 Pt 2):583–590. doi: 10.1016/0092-8674(85)90230-2. [DOI] [PubMed] [Google Scholar]
  10. Gyllensten U. B., Erlich H. A. Generation of single-stranded DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7652–7656. doi: 10.1073/pnas.85.20.7652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hanks S. K., Quinn A. M., Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988 Jul 1;241(4861):42–52. doi: 10.1126/science.3291115. [DOI] [PubMed] [Google Scholar]
  12. Honegger A. M., Kris R. M., Ullrich A., Schlessinger J. Evidence that autophosphorylation of solubilized receptors for epidermal growth factor is mediated by intermolecular cross-phosphorylation. Proc Natl Acad Sci U S A. 1989 Feb;86(3):925–929. doi: 10.1073/pnas.86.3.925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kammermeyer K. L., Wadsworth S. C. Expression of Drosophila epidermal growth factor receptor homologue in mitotic cell populations. Development. 1987 Jun;100(2):201–210. doi: 10.1242/dev.100.2.201. [DOI] [PubMed] [Google Scholar]
  14. Kraus M. H., Issing W., Miki T., Popescu N. C., Aaronson S. A. Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9193–9197. doi: 10.1073/pnas.86.23.9193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lev Z., Shilo B. Z., Kimchie Z. Developmental changes in expression of the Drosophila melanogaster epidermal growth factor receptor gene. Dev Biol. 1985 Aug;110(2):499–502. doi: 10.1016/0012-1606(85)90107-1. [DOI] [PubMed] [Google Scholar]
  16. Livneh E., Glazer L., Segal D., Schlessinger J., Shilo B. Z. The Drosophila EGF receptor gene homolog: conservation of both hormone binding and kinase domains. Cell. 1985 Mar;40(3):599–607. doi: 10.1016/0092-8674(85)90208-9. [DOI] [PubMed] [Google Scholar]
  17. Manseau L. J., Schüpbach T. cappuccino and spire: two unique maternal-effect loci required for both the anteroposterior and dorsoventral patterns of the Drosophila embryo. Genes Dev. 1989 Sep;3(9):1437–1452. doi: 10.1101/gad.3.9.1437. [DOI] [PubMed] [Google Scholar]
  18. Margolis B., Li N., Koch A., Mohammadi M., Hurwitz D. R., Zilberstein A., Ullrich A., Pawson T., Schlessinger J. The tyrosine phosphorylated carboxyterminus of the EGF receptor is a binding site for GAP and PLC-gamma. EMBO J. 1990 Dec;9(13):4375–4380. doi: 10.1002/j.1460-2075.1990.tb07887.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Myers R. M., Maniatis T., Lerman L. S. Detection and localization of single base changes by denaturing gradient gel electrophoresis. Methods Enzymol. 1987;155:501–527. doi: 10.1016/0076-6879(87)55033-9. [DOI] [PubMed] [Google Scholar]
  20. Nocka K., Tan J. C., Chiu E., Chu T. Y., Ray P., Traktman P., Besmer P. Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W37, Wv, W41 and W. EMBO J. 1990 Jun;9(6):1805–1813. doi: 10.1002/j.1460-2075.1990.tb08305.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Plowman G. D., Whitney G. S., Neubauer M. G., Green J. M., McDonald V. L., Todaro G. J., Shoyab M. Molecular cloning and expression of an additional epidermal growth factor receptor-related gene. Proc Natl Acad Sci U S A. 1990 Jul;87(13):4905–4909. doi: 10.1073/pnas.87.13.4905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Price J. V., Clifford R. J., Schüpbach T. The maternal ventralizing locus torpedo is allelic to faint little ball, an embryonic lethal, and encodes the Drosophila EGF receptor homolog. Cell. 1989 Mar 24;56(6):1085–1092. doi: 10.1016/0092-8674(89)90641-7. [DOI] [PubMed] [Google Scholar]
  23. Schejter E. D., Segal D., Glazer L., Shilo B. Z. Alternative 5' exons and tissue-specific expression of the Drosophila EGF receptor homolog transcripts. Cell. 1986 Sep 26;46(7):1091–1101. doi: 10.1016/0092-8674(86)90709-9. [DOI] [PubMed] [Google Scholar]
  24. Schlessinger J. Signal transduction by allosteric receptor oligomerization. Trends Biochem Sci. 1988 Nov;13(11):443–447. doi: 10.1016/0968-0004(88)90219-8. [DOI] [PubMed] [Google Scholar]
  25. Schüpbach T. Germ line and soma cooperate during oogenesis to establish the dorsoventral pattern of egg shell and embryo in Drosophila melanogaster. Cell. 1987 Jun 5;49(5):699–707. doi: 10.1016/0092-8674(87)90546-0. [DOI] [PubMed] [Google Scholar]
  26. Skolnik E. Y., Margolis B., Mohammadi M., Lowenstein E., Fischer R., Drepps A., Ullrich A., Schlessinger J. Cloning of PI3 kinase-associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases. Cell. 1991 Apr 5;65(1):83–90. doi: 10.1016/0092-8674(91)90410-z. [DOI] [PubMed] [Google Scholar]
  27. Ullrich A., Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990 Apr 20;61(2):203–212. doi: 10.1016/0092-8674(90)90801-k. [DOI] [PubMed] [Google Scholar]
  28. Wharton K. A., Johansen K. M., Xu T., Artavanis-Tsakonas S. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell. 1985 Dec;43(3 Pt 2):567–581. doi: 10.1016/0092-8674(85)90229-6. [DOI] [PubMed] [Google Scholar]
  29. Wides R. J., Zak N. B., Shilo B. Z. Enhancement of tyrosine kinase activity of the Drosophila epidermal growth factor receptor homolog by alterations of the transmembrane domain. Eur J Biochem. 1990 May 20;189(3):637–645. doi: 10.1111/j.1432-1033.1990.tb15532.x. [DOI] [PubMed] [Google Scholar]
  30. Zak N. B., Wides R. J., Schejter E. D., Raz E., Shilo B. Z. Localization of the DER/flb protein in embryos: implications on the faint little ball lethal phenotype. Development. 1990 Aug;109(4):865–874. doi: 10.1242/dev.109.4.865. [DOI] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES