Differential effects of Cbl isoforms on Egfr signaling in Drosophila

Li Mei Pai, Pei Yu Wang, Shu Ru Chen, Gail Barcelo, Wei Ling Chang, Laura Nilson, Trudi Schüpbach

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)450-462
Number of pages13
JournalMechanisms of Development
Issue number6
StatePublished - Jun 2006

All Science Journal Classification (ASJC) codes

  • Embryology
  • Developmental Biology


  • D-Cbl
  • Drosophila
  • Egfr
  • Endocytosis
  • Follicle cells


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