title: Nectin-4 co-stimulates the prolactin receptor by interacting with SOCS1 and inhibiting its activity on the JAK2-STAT5a signaling pathway.
abstract: Cell-surface cytokine receptors are regulated by theircis-interacting stimulatory and inhibitory co-receptors. We previously showed that the Ig-like cell-adhesion molecule nectin-4cis-interacts with the prolactin receptor through the extracellular region and stimulates prolactin-induced prolactin receptor activation and signaling, resulting in alveolar development in the mouse mammary gland. However, it remains unknown how this interaction stimulates these effects. We show here that thecis-interaction of the extracellular region of nectin-4 with the prolactin receptor was not sufficient for eliciting these effects and that the cytoplasmic region of nectin-4 was also required for this interaction. The cytoplasmic region of nectin-4 directly interacted with suppressor of cytokine signaling 1 (SOCS1), but not SOCS3, JAK2, or STAT5a, and inhibited the interaction of SOCS1 with JAK2, eventually resulting in the increased phosphorylation of STAT5a. The juxtamembrane region of nectin-4 interacted with the Src homology 2 domain of SOCS1. Both the interaction of nectin-4 with the extracellular region of the prolactin receptor and the interaction of SOCS1 with the cytoplasmic region of nectin-4 were required for the stimulatory effect of nectin-4 on the prolactin-induced prolactin receptor activation. The third Ig-like domain of nectin-4 and the second fibronectin type III domain of the prolactin receptor were involved in thiscis-interaction, and both the extracellular and transmembrane regions of nectin-4 and the prolactin receptor were required for this direct interaction. These results indicate that nectin-4 serves as a stimulatory co-receptor for the prolactin receptor by regulating the feedback inhibition of SOCS1 in the JAK2-STAT5a signaling pathway.
authors.affiliation: From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047.|the Health Metrics Development Team, RIKEN Compass to Healthy Life Research Complex Program, 6-7-1 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, and.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Maruoka
authors.affiliation: From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047.
authors.forename: Shin
authors.initials: S
authors.lastname: Kedashiro
authors.affiliation: From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, mizutani@med.kobe-u.ac.jp.
authors.forename: Kiyohito
authors.initials: K
authors.lastname: Mizutani
authors.affiliation: From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, ytakai@med.kobe-u.ac.jp.|the Pathophysiological and Health Science Team, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Takai
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D011388:Prolactin / Q000378:metabolism; D011981:Receptors, Prolactin / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000075983:Nectins
chemical_list: D015815:Cell Adhesion Molecules; D005353:Fibronectins; D053614:Janus Kinase 2; D011388:Prolactin; D011981:Receptors, Prolactin; D050799:STAT5 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D025521:Tumor Suppressor Proteins; C108944:SOCS1 protein, human; C494092:STAT5A protein, human; C491590:Socs1 protein, mouse; C494093:Stat5a protein, mouse; C486698:Nectin4 protein, mouse; D000075983:Nectins; C442228:NECTIN4 protein, human; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse
keywords: Janus kinase (JAK); STAT transcription factor; cell adhesion; cell surface receptor; cell-cell interaction; nectin; prolactin; suppressor of cytokine signaling 1 (SOCS1)