title: Prolactin stimulates ubiquitination, initial internalization, and degradation of its receptor via catalytic activation of Janus kinase 2.
abstract: Prolactin (PRL) activates its receptor to initiate signal transduction pathways (including activation of Janus kinases, Jak) but also stimulates downregulation of this receptor to limit the magnitude and duration of signaling. Degradation of the long form of PRL receptor (PRLr) depends on its phosphorylation on Ser349 that is required to facilitate PRLr ubiquitination. Signaling events that mediate PRL-induced degradation of PRLr remain to be elucidated. Here, we investigated the role of Jak2 activity in ligand-triggered increase of PRLr phosphorylation on Ser349, PRLr ubiquitination, endocytosis, and degradation. Using Jak2 reconstitution in Jak2-null cells as well as pharmacologic approaches, we found that treatment with PRL (but not with PRLr antagonist) promotes phosphorylation of PRLr on Ser349 and accelerates endocytosis of PRLr. Furthermore, PRL-stimulated PRLr phosphorylation, endocytosis, and degradation in Jak2-null cells reconstituted with wild type but not with catalytically inactive Jak2. We discuss how Jak2-mediated signaling might be transduced into Ser349 phosphorylation of PRLr as well as its ubiquitination and endocytosis.
authors.affiliation: Department of Animal Biology and Mari Lowe Center for Comparative Oncology Research Cell, University of Pennsylvania, 380 S University Avenue, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Swaminathan
authors.forename: Bentley
authors.initials: B
authors.lastname: Varghese
authors.forename: Chellappagounder
authors.initials: C
authors.lastname: Thangavel
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Carbone
authors.forename: Alexander
authors.initials: A
authors.lastname: Plotnikov
authors.forename: K G Suresh
authors.initials: KG
authors.lastname: Kumar
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jablonski
authors.forename: Charles V
authors.initials: CV
authors.lastname: Clevenger
authors.forename: Vincent
authors.initials: V
authors.lastname: Goffin
authors.forename: Luqin
authors.initials: L
authors.lastname: Deng
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Frank
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
mesh_terms: D002384:Catalysis; D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D053614:Janus Kinase 2 / Q000172:deficiency / Q000378:metabolism*; D008024:Ligands; D010766:Phosphorylation / Q000187:drug effects; D011388:Prolactin / Q000494:pharmacology / Q000502:physiology*; D011981:Receptors, Prolactin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology*
chemical_list: D008024:Ligands; D011981:Receptors, Prolactin; D011388:Prolactin; D053614:Janus Kinase 2