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An AGEF-1/Arf GTPase/AP-1 Ensemble Antagonizes LET-23 EGFR Basolateral Localization and Signaling during Vulva Induction

English version České info

In the nematode, Caenorhabditis elegans, an evolutionarily conserved Epidermal Growth Factor Receptor (EGFR) signaling pathway is required to induce three epithelial cells to initiate a program of vulva development. EGFR on the basolateral membrane is essential to engage and transmit this signal. Here we demonstrate that AGEF-1 and the AP-1 clathrin adaptor complex function with two Arf GTPases to regulate EGFR localization and signaling. In humans, EGFR also localizes to the basolateral membrane of epithelial cells, and excessive EGFR signaling is a major driver of cancer. In C. elegans, we show that loss of AGEF-1 results in an increase in basolateral EGFR localization in the vulva precursor cells, and in sensitized genetic backgrounds, a corresponding increase in vulva induction. While the human AGEF-1 proteins, BIG1 and BIG2, have not been previously implicated in EGFR signaling and cancer, mutations in BIG2 are causal of periventricular heterotopia, a condition whereby neurons fail to migrate to the cerebral cortex during brain development. As migrating neurons require polarized protein localization, BIG2 and AGEF-1 may have similar functions in these polarized cell types.

Vyšlo v časopise: An AGEF-1/Arf GTPase/AP-1 Ensemble Antagonizes LET-23 EGFR Basolateral Localization and Signaling during Vulva Induction. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004728
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004728

Souhrn

In the nematode, Caenorhabditis elegans, an evolutionarily conserved Epidermal Growth Factor Receptor (EGFR) signaling pathway is required to induce three epithelial cells to initiate a program of vulva development. EGFR on the basolateral membrane is essential to engage and transmit this signal. Here we demonstrate that AGEF-1 and the AP-1 clathrin adaptor complex function with two Arf GTPases to regulate EGFR localization and signaling. In humans, EGFR also localizes to the basolateral membrane of epithelial cells, and excessive EGFR signaling is a major driver of cancer. In C. elegans, we show that loss of AGEF-1 results in an increase in basolateral EGFR localization in the vulva precursor cells, and in sensitized genetic backgrounds, a corresponding increase in vulva induction. While the human AGEF-1 proteins, BIG1 and BIG2, have not been previously implicated in EGFR signaling and cancer, mutations in BIG2 are causal of periventricular heterotopia, a condition whereby neurons fail to migrate to the cerebral cortex during brain development. As migrating neurons require polarized protein localization, BIG2 and AGEF-1 may have similar functions in these polarized cell types.

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