{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T19:40:30Z","timestamp":1791142830603,"version":"4.1.0"},"reference-count":45,"publisher":"The Company of Biologists","issue":"22","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2005,11,15]]},"abstract":"<jats:p>A novel mode of crosstalk between the EGFR-Ras-MAPK and LIN-12\/Notch pathways occurs during the patterning of a row of vulval precursor cells(VPCs) in Caenorhabditis elegans: activation of the EGFR-Ras-MAPK pathway in the central VPC promotes endocytosis and degradation of LIN-12 protein. LIN-12 downregulation in the central VPC is a prerequisite for the activity of the lateral signal, which activates LIN-12 in neighboring VPCs. Here we characterize cis-acting targeting sequences in the LIN-12 intracellular domain and find that in addition to a di-leucine motif,serine\/threonine residues are important for internalization and lysine residues are important for post-internalization trafficking and degradation. We also identify two trans-acting factors that are required for post-internalization trafficking and degradation: ALX-1, a homolog of yeast Bro1p and mammalian Alix and the WWP-1\/Su(dx)\/Itch ubiquitin ligase. By examining the effects of mutated forms of LIN-12 and reduced wwp-1or alx-1 activity on subcellular localization and activity of LIN-12,we provide evidence that the lateral signal-inhibiting activity of LIN-12 resides in the extracellular domain and occurs at the apical surface of the VPCs.<\/jats:p>","DOI":"10.1242\/dev.02076","type":"journal-article","created":{"date-parts":[[2005,10,20]],"date-time":"2005-10-20T09:46:39Z","timestamp":1129801599000},"page":"5081-5092","source":"Crossref","is-referenced-by-count":61,"title":["LIN-12\/Notch trafficking and regulation of DSL ligand activity during vulval induction in\n                    <i>Caenorhabditis elegans<\/i>"],"prefix":"10.1242","volume":"132","author":[{"given":"Daniel D.","family":"Shaye","sequence":"first","affiliation":[{"name":"Howard Hughes Medical Institute, Columbia University, New York, NY 10032,USA"},{"name":"Department of Genetics and Development, Columbia University, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iva","family":"Greenwald","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Columbia University, New York, NY 10032,USA"},{"name":"Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042605191866000_REF1","unstructured":"Berset, T., Hoier, E. 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