title: KIBRA interacts with discoidin domain receptor 1 to modulate collagen-induced signalling.
abstract: Mammary gland development is coupled to reproductive events by hormonal cues of ovarian and pituitary origin, which activate a genomic regulatory network. Identification of the components and regulatory links that comprise this network will provide the basis for defining the network's dynamic response during normal development and its perturbation during breast carcinogenesis. In this study KIBRA was identified as a transcript showing decreased expression associated with failed mammary gland development in Prlr knockout mammary epithelium. It is strongly up-regulated during pregnancy, falls during lactation and is again up-regulated during involution of the gland at weaning. A bioinformatic approach was undertaken to identify potential binding partners which interact with the WW domains of KIBRA. We show that KIBRA binds to a WW domain binding motif, PPxY, in the tyrosine kinase receptor DDR1, and dissociates upon treatment with the DDR1 ligands collagen type I or IV. In addition we show that KIBRA and DDR1 also interact with PKCz to form a trimeric complex. Finally, overexpression and knockdown studies demonstrate that KIBRA promotes the collagen-stimulated activation of the MAPK cascade. Thus KIBRA may play a role in how the reproductive state influences the mammary epithelial cell to respond to changing cell-context information, such as experienced during the tissue remodeling events of mammary gland development.
authors.affiliation: Development Group, Cancer Research Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: Heidi N
authors.initials: HN
authors.lastname: Hilton
authors.forename: Prudence M
authors.initials: PM
authors.lastname: Stanford
authors.forename: Jessica
authors.initials: J
authors.lastname: Harris
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Oakes
authors.forename: Warren
authors.initials: W
authors.lastname: Kaplan
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Daly
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ormandy
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000502:physiology*; D000070818:Discoidin Domain Receptors; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000502:physiology; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism; D042361:Mammary Glands, Human / Q000254:growth & development / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics; D010750:Phosphoproteins; D011247:Pregnancy; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism* / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism*; D011981:Receptors, Prolactin / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011506:Proteins; D011975:Receptors, Mitogen; D011981:Receptors, Prolactin; C513637:WWC1 protein, human; D003094:Collagen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases