{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T12:35:23Z","timestamp":1791117323799,"version":"4.1.0"},"reference-count":31,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5658","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2004,1,30]]},"abstract":"<jats:p>\n                    The\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    vulva is an important paradigm for cell-cell interactions in animal development. The fates of six vulval precursor cells are patterned through the action of the epidermal growth factor receptor\u2013mitogen-activated protein kinase (EGFR-MAPK) inductive signaling pathway, which specifies the 1\u00b0 fate, and the LIN-12\/Notch lateral signaling pathway, which specifies the 2\u00b0 fate. Here, we provide evidence that the inductive signal is spatially graded and initially activates the EGFR-MAPK pathway in the prospective 2\u00b0 cells. Subsequently, this effect is counteracted by the expression of multiple new negative regulators of the EGFR-MAPK pathway, under direct transcriptional control of the LIN-12\u2013mediated lateral signal.\n                  <\/jats:p>","DOI":"10.1126\/science.1091639","type":"journal-article","created":{"date-parts":[[2004,1,29]],"date-time":"2004-01-29T17:58:21Z","timestamp":1075399101000},"page":"663-666","source":"Crossref","is-referenced-by-count":224,"title":["Crosstalk Between the EGFR and LIN-12\/Notch Pathways in\n                    <i>C. elegans<\/i>\n                    Vulval Development"],"prefix":"10.1126","volume":"303","author":[{"given":"Andrew S.","family":"Yoo","sequence":"first","affiliation":[{"name":"Integrated Program in Cellular, Molecular, and Biophysical Studies, Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, 701 West 168th Street, Room 720, New York, NY 10032, USA."},{"name":"Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, 701 West 168th Street, Room 720, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Bais","sequence":"additional","affiliation":[{"name":"Integrated Program in Cellular, Molecular, and Biophysical Studies, Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, 701 West 168th Street, Room 720, New York, NY 10032, USA."},{"name":"Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, 701 West 168th Street, Room 720, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iva","family":"Greenwald","sequence":"additional","affiliation":[{"name":"Integrated Program in Cellular, Molecular, and Biophysical Studies, Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, 701 West 168th Street, Room 720, New York, NY 10032, USA."},{"name":"Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, 701 West 168th Street, Room 720, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","first-page":"519","year":"1997","unstructured":"I. Greenwald, in D. L. Riddle, T. Blumenthal, B. J. Meyer, J. R. Priess, Eds., C. ELEGANS II (Cold Spring Harbor Laboratory Press, Plainview, NY, 1997), pp. 519\u2013542.","journal-title":"C. ELEGANS II"},{"key":"e_1_3_2_3_2","unstructured":"N. Chen I. Greenwald unpublished observations."},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(86)90842-1"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/375142a0"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.121.8.2655"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.125.6.1083"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/153.3.1257"},{"key":"e_1_3_2_9_2","unstructured":"A. S. Yoo et al. data not shown."},{"key":"e_1_3_2_10_2","unstructured":"Materials and methods are available as supporting material on Science Online."},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.122.5.1373"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.152320899"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(05)00001-8"},{"key":"e_1_3_2_14_2","unstructured":"Four of the five new genes that behave as negative regulators of the EGFR-MAPK pathway in the VPCs in functional assays have mammalian orthologs defined as highest scoring \u201chits\u201d in reciprocal Basic Local Alignment Search Tool (BLAST) searches: LST-2 (R160.7) = XM 035371.4 and a set of related sequences LST-3 (Y37A1B.1) = AK023438 and a set of related sequences LST-4 (Y37A1B.2) = sorting nexin 9\/18 and DPY-23 (R160.1) = \u03bc subunit of the Clathrin Adaptor Protein Complex 2. Recent biochemical data for the orthologs of DPY-23 and LST-4 in cultured cells have suggested roles for them in the degradation of EGFR ( 21 22 ); for these genes our C. elegans data provide evidence for their roles as negative regulators of EGFR activity in vivo. The mammalian orthologs of LST-2 and LST-3 have not been previously implicated in negative regulation of EGFR-MAPK signaling. Analysis of potential functional domains with the Simple Modular Architecture Research Tool (SMART) ( 23 ) reveals that LST-2 contains a FYVE domain a membrane targeting domain that binds specifically to a phospholipid that resides mainly in endosomal membranes ( 24 ) and therefore may influence the endocytic trafficking of LET-23 or the subcellular localization of other components of the EGFR-MAPK pathway. LST-3 contains SAF-A\/B Acinus and PIAS (SAP) domains a motif found in DNA binding proteins and thus does not suggest a potential direct role in modulating EGFR-MAPK activity. LST-1 (T22A3.3) does not have a recognizable mammalian ortholog; it was found in a genome-wide yeast two-hybrid screen for proteins that interact with the MAPK ortholog MPK-1 ( 25 ) and hence may act directly on MAP kinase."},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1055642"},{"key":"e_1_3_2_16_2","unstructured":"Most of the lst gene transcriptional reporters were made by a polymerase chain reaction fusion protocol ( 26 ) and extrachromosomal arrays were generated in a pha-1(e2123ts) background using pha-1( + ) as a transformation marker ( 27 ). For extrachromosomal arrays more than one line was scored as indicated and we mitigated against the potential lack of expression in P5.p or P7.p due to mosaicism by including data only for animals in which expression (even if faint) could be seen in P3.p P4.p and P8.p or for both P5.p and P7.p. The exception to these general procedures was lst-1 for which conventional constructs and integrated transgenes were used. For transgene details see ( 9 )."},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.9.24.3149"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.117.3.1113"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.125.22.4531"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01234"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(03)00052-7"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110329200"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.9.2240"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/30.1.242"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0854.2004.00071.x"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.287.5450.116"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.2144\/02324bm01"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/22.9.1762"},{"key":"e_1_3_2_29_2","unstructured":"G. Garriga personal communication."},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/27579"},{"key":"e_1_3_2_31_2","unstructured":"WormBase: The Biology and Genome of C. elegans www.wormbase.org."},{"key":"e_1_3_2_32_2","unstructured":"We thank A. Wong for initial and encouraging computational analyses to identify potential LIN-12 targets H. Yu for collaborating on the development of Cluster Analyzer for Transcription Sites (CATS) and X. Zhou for generating transgenic lines. We thank the Caenorhabditis Genetic Center for strains Y. Kohara for cosmids and A. Fire and M. Vidal for plasmids. We appreciate the comments on the manuscript from O. Hobert S. Jarriault R. Mann and D. Shaye. A.Y. was supported by a fellowship from the National Sciences and Engineering Research Council of Canada (NSERC) and in part by NIH CA095389 (to I.G.). C.B. is a postdoctoral associate and I.G. is an investigator of the Howard Hughes Medical Institute."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.1091639","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T22:52:43Z","timestamp":1704840763000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.1091639"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,1,30]]},"references-count":31,"journal-issue":{"issue":"5658","published-print":{"date-parts":[[2004,1,30]]}},"alternative-id":["10.1126\/science.1091639"],"URL":"https:\/\/doi.org\/10.1126\/science.1091639","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1017909.210461","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.1017909.207512","asserted-by":"object"}]},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,1,30]]}}}