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PMID:18190796

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Citation

Hilton, HN, Stanford, PM, Harris, J, Oakes, SR, Kaplan, W, Daly, RJ and Ormandy, CJ (2008) KIBRA interacts with discoidin domain receptor 1 to modulate collagen-induced signalling. Biochim. Biophys. Acta 1783:383-93

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.

Links

PubMed Online version:10.1016/j.bbamcr.2007.12.007

Keywords

Animals; Cell Proliferation; Cells, Cultured; Collagen/physiology; Enzyme Activation/physiology; Female; HeLa Cells; Humans; Intracellular Signaling Peptides and Proteins; MAP Kinase Signaling System/physiology; Mammary Glands, Animal/growth & development; Mammary Glands, Animal/metabolism; Mammary Glands, Human/growth & development; Mammary Glands, Human/metabolism; Mammary Glands, Human/physiology; Mice; Mice, Knockout; Morphogenesis/genetics; Phosphoproteins; Pregnancy; Protein Binding; Proteins/metabolism; Proteins/physiology; Receptor Protein-Tyrosine Kinases/genetics; Receptor Protein-Tyrosine Kinases/metabolism; Receptors, Mitogen/genetics; Receptors, Mitogen/metabolism; Receptors, Prolactin/genetics; Signal Transduction/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:KPCZ

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8IX03

F

Seeded From UniProt

complete

HUMAN:DDR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8IX03

F

Seeded From UniProt

complete

MOUSE:KIBRA

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KIBRA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q08345

F

Seeded From UniProt

complete

HUMAN:KIBRA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q05513

F

Seeded From UniProt

complete

HUMAN:KIBRA

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KIBRA

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KIBRA

located_in

GO:0032587: ruffle membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KIBRA

involved_in

GO:0043410: positive regulation of MAPK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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