Editors' ChoiceEndocytosis

Pathways Talk at Endosomes

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Science Signaling  24 Feb 2009:
Vol. 2, Issue 59, pp. ec71
DOI: 10.1126/scisignal.259ec71

Endocytosis plays complex roles in Notch signaling, with endocytosis of the signal-producing cell contributing to activation of the receptor in the signal-receiving cell; the activated receptor is also endocytosed by the receiving cell, which contributes to signaling. Endocytosis is also important for Wnt [known as Wingless (Wg) in flies] signaling, with Wg, its receptor Frizzled, and downstream signaling components colocalizing in endosomes. Nagaraj and Banerjee describe a mechanism by which signaling in flies by receptor tyrosine kinase pathways, specifically EGFR (epidermal growth factor receptor), regulates Wg and Notch signaling at endosomes (see Shilo for commentary). The gene encoding phyllopod (Phyl) is stimulated by EGFR signaling, and Phyl has a reported function of promoting the degradation of a transcriptional repressor, Tramtrack (ttk). Nagaraj and Banerjee report a new function for Phyl in promoting delivery of Wg and Notch from early endosomes to lysosomes in the developing fly eye. The Notch intracellular domain, the Notch ligand Delta, and Wg accumulated in punctate vesicles in the developing eyes of phyl mutants. The phenotypes of the phyl mutants were the same as those produced by overexpression of Delta—loss of photoreceptor cells R1, R6, and R7 and overspecification of nonneuronal cells. In the phyl mutant eyes, Wg and Notch colocalized with early endosomal markers and failed to reach lysosomes. Ttk is not involved in the endosomal trafficking defect observed in the phyl mutant cells. Forced expression of activated EGFR, forced expression of activated Ras (downstream of EGFR), or forced expression of Phyl restored proper cell specification in a background of constitutively activated Notch, thus confirming the connection between EGFR, Phyl, and Notch. Eye phenotypes associated with excessive EGFR activity were phenocopied by forced expression of Phyl and, in cells in which temperature-sensitive EGFR was expressed, Wg accumulated in endocytic vesicles. Thus, one way that EGFR signaling controls Notch and Wg activity is by promoting their delivery to lysosomes through the induction of the gene encoding Phyl.

R. Nagaraj, U. Banerjee, Regulation of Notch and Wingless signalling by phyllopod, a transcriptional target of the EGFR pathway. EMBO J. 28, 337–346 (2009). [PubMed]

B.-Z. Shilo, Phyllopod at the intersection of developmental signalling pathways. EMBO J. 28, 311–312 (2009). [PubMed]

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