Differential effects of Cbl isoforms on Egfr signaling in Drosophila.
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.
Pai
Li-Mei
LM
Department of Biochemistry, Chang-Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan, ROC. pai@mail.cgu.edu.tw
Wang
Pei-Yu
PY
Chen
Shu-Ru
SR
Barcelo
Gail
G
Chang
Wei-Ling
WL
Nilson
Laura
L
Schüpbach
Trudi
T
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
D029721:Drosophila Proteins; D020033:Protein Isoforms; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors; C106411:Cbl protein, Drosophila