title: RasGRP1 opposes proliferative EGFR-SOS1-Ras signals and restricts intestinal epithelial cell growth.
abstract: The character of EGFR signals can influence cell fate but mechanistic insights into intestinal EGFR-Ras signalling are limited. Here we show that two distinct Ras nucleotide exchange factors, RasGRP1 and SOS1, lie downstream of EGFR but act in functional opposition. RasGRP1 is expressed in intestinal crypts where it restricts epithelial growth. High RasGRP1 expression in colorectal cancer (CRC) patient samples correlates with a better clinical outcome. Biochemically, we find that RasGRP1 creates a negative feedback loop that limits proliferative EGFR-SOS1-Ras signals in CRC cells. Genetic Rasgrp1 depletion from mice with either an activating mutation in KRas or with aberrant Wnt signalling due to a mutation in Apc resulted in both cases in exacerbated Ras-ERK signalling and cell proliferation. The unexpected opposing cell biological effects of EGFR-RasGRP1 and EGFR-SOS1 signals in the same cell shed light on the intricacy of EGFR-Ras signalling in normal epithelium and carcinoma.
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Depeille
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Henricks
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Robert A H
authors.initials: RA
authors.lastname: van de Ven
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Ed
authors.initials: E
authors.lastname: Lemmens
authors.affiliation: 1] Department of Anatomy, University of California, San Francisco, San Francisco, California 94143, USA [2] Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Matli
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
authors.affiliation: Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
authors.affiliation: Department of Surgery, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: David
authors.initials: D
authors.lastname: Donner
authors.affiliation: Department of Surgery, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Warren
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Jeroen P
authors.initials: JP
authors.lastname: Roose
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D020837:SOS1 Protein / Q000378:metabolism*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D020662:Guanine Nucleotide Exchange Factors; D034741:RNA, Small Interfering; C112278:Rasgrp1 protein, mouse; D020837:SOS1 Protein; D051153:Wnt Proteins; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)