A novel and functional interaction between cyclophilin A and prolactin receptor.
Precedent data have revealed that peptidyl isomerases can modulate the function of cell-surface receptors, but no such interactions have been previously shown for the members of the cytokine receptor superfamily. We demonstrate here that a functional interaction occurs between the prolactin receptor (PRLR) and peptidyl prolyl cis/trans isomerase cyclophilin A (CypA). CypA was co-immunoprecipitated with the PRLR in vivo from the breast epithelial cell line T47D and Chinese hamster ovary transfectants overexpressing transfected human PRLR. In addition, in vitro binding assays demonstrated a direct interaction of CypA with the PRLR, in the presence or absence of cyclosporine. Co-immunoprecipitation studies also showed an association of CypA with Jak2. Functional analysis revealed that overexpression of CypA inhibited PRL-induced Rac activation, while simultaneously prolonging Jak2 phosphorylation. These proximal actions had profound downstream effects: CypA overexpression significantly enhanced the basal and PRL-stimulated expression from a beta-casein reporter construct. Hence, the interaction between CypA and the PRLR plays a differential regulatory role in the various signaling pathways leading from the PRLR.
Syed
Farhat
F
Department of Pathology, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
Rycyzyn
Michael A
MA
Westgate
Liz
L
Clevenger
Charles V
CV
D000818:Animals; D001940:Breast / Q000166:cytology; D016466:CHO Cells; D002364:Caseins / Q000378:metabolism; D006224:Cricetinae; D021984:Cyclophilin A / Q000378:metabolism* / Q000494:pharmacology; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology; D006801:Humans; D053614:Janus Kinase 2; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D002364:Caseins; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D020830:rac1 GTP-Binding Protein; D021984:Cyclophilin A