title: Differential effects of Cbl isoforms on Egfr signaling in Drosophila.
abstract: The Cbl family of proteins downregulate epidermal growth factor receptor (Egfr) signaling via receptor internalization and destruction. These proteins contain two functional domains, a RING finger domain with E3 ligase activity, and a proline rich domain mediating the formation of protein complexes. The Drosophila cbl gene encodes two isoforms, D-CblS and D-CblL. While both contain a RING finger domain, the proline rich domain is absent from D-CblS. We demonstrate that expression of either isoform is sufficient to rescue both the lethality of a D-cbl null mutant and the adult phenotypes characteristic of Egfr hyperactivation, suggesting that both isoforms downregulate Egfr signaling. Interestingly, targeted overexpression of D-CblL, but not D-CblS, results in phenotypes characteristic of reduced Egfr signaling and suppresses the effect of constitutive Egfr activation. The level of D-CblL was significantly correlated with the phenotypic severity of reduced Egfr signaling, suggesting that D-CblL controls the efficiency of downregulation of Egfr signaling. Furthermore, reduced dynamin function suppresses the effects of D-CblL overexpression in follicle cells, suggesting that D-CblL promotes internalization of activated receptors. D-CblL is detected in a punctate cytoplasmic pattern, whereas D-CblS is mainly localized at the follicle cell cortex. Therefore, D-CblS and D-CblL may downregulate Egfr through distinct mechanisms.
authors.affiliation: Department of Biochemistry, Chang-Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan, ROC. pai@mail.cgu.edu.tw
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Pai
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Wang
authors.forename: Shu-Ru
authors.initials: SR
authors.lastname: Chen
authors.forename: Gail
authors.initials: G
authors.lastname: Barcelo
authors.forename: Wei-Ling
authors.initials: WL
authors.lastname: Chang
authors.forename: Laura
authors.initials: L
authors.lastname: Nilson
authors.forename: Trudi
authors.initials: T
authors.lastname: Schüpbach
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D019521:Body Patterning; D029721:Drosophila Proteins / Q000737:chemistry* / Q000502:physiology*; D004331:Drosophila melanogaster; D004705:Endocytosis; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D010053:Ovary / Q000378:metabolism; D010641:Phenotype; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D050721:Proto-Oncogene Proteins c-cbl / Q000737:chemistry* / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D029721:Drosophila Proteins; D020033:Protein Isoforms; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors; C106411:Cbl protein, Drosophila