TY - JOUR
T1 - Differential effects of Cbl isoforms on Egfr signaling in Drosophila
AU - Pai, Li Mei
AU - Wang, Pei Yu
AU - Chen, Shu Ru
AU - Barcelo, Gail
AU - Chang, Wei Ling
AU - Nilson, Laura
AU - Schüpbach, Trudi
N1 - Funding Information:
We thank Norbert Perrimon, Marcos González-Gaitán, Cheng-Ting Chien, and Tze-Bin Chou for providing fly stocks, Matthew Freeman and David Stein for cDNAs, and Jennifer Goodrich and Jörg Grosshans for the ovarian cDNA libraries. Many thanks to Marty Marlow for help with monoclonal antibody preparation. We also thank Chih-Chun Chen for excellent assistance with confocal microscopy. We appreciate generous support from Yu-Sun Chang, and Henry Sun during initial set-up of the laboratory. We are grateful to Mark Peifer, Y. Henry Sun, Cheng-Ting Chien, and Chien-Kuo Lee for critical reading of this manuscript. This work was supported by grants from Chang-Gung University (CMRP1186 and CMRPD140041) and the National Science Council of Republic of China (NSC 91-2311-B-182-006) to L.P., and by USPHS grant PO1CA41086 to T.S. and the Howard Hughes Medical Institute.
PY - 2006/6
Y1 - 2006/6
N2 - 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.
AB - 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.
KW - D-Cbl
KW - Drosophila
KW - Egfr
KW - Endocytosis
KW - Follicle cells
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U2 - 10.1016/j.mod.2006.04.001
DO - 10.1016/j.mod.2006.04.001
M3 - Article
C2 - 16844358
AN - SCOPUS:33746808221
SN - 0925-4773
VL - 123
SP - 450
EP - 462
JO - Mechanisms of Development
JF - Mechanisms of Development
IS - 6
ER -