PMID:12388746

Citation	Park, DS, Lee, H, Frank, PG, Razani, B, Nguyen, AV, Parlow, AF, Russell, RG, Hulit, J, Pestell, RG and Lisanti, MP (2002) Caveolin-1-deficient mice show accelerated mammary gland development during pregnancy, premature lactation, and hyperactivation of the Jak-2/STAT5a signaling cascade. Mol. Biol. Cell 13:3416-30
Abstract	It is well established that mammary gland development and lactation are tightly controlled by prolactin signaling. Binding of prolactin to its cognate receptor (Prl-R) leads to activation of the Jak-2 tyrosine kinase and the recruitment/tyrosine phosphorylation of STAT5a. However, the mechanisms for attenuating the Prl-R/Jak-2/STAT5a signaling cascade are just now being elucidated. Here, we present evidence that caveolin-1 functions as a novel suppressor of cytokine signaling in the mammary gland, akin to the SOCS family of proteins. Specifically, we show that caveolin-1 expression blocks prolactin-induced activation of a STAT5a-responsive luciferase reporter in mammary epithelial cells. Furthermore, caveolin-1 expression inhibited prolactin-induced STAT5a tyrosine phosphorylation and DNA binding activity, suggesting that caveolin-1 may negatively regulate the Jak-2 tyrosine kinase. Because the caveolin-scaffolding domain bears a striking resemblance to the SOCS pseudosubstrate domain, we examined whether Jak-2 associates with caveolin-1. In accordance with this homology, we demonstrate that Jak-2 cofractionates and coimmunoprecipitates with caveolin-1. We next tested the in vivo relevance of these findings using female Cav-1 (-/-) null mice. If caveolin-1 normally functions as a suppressor of cytokine signaling in the mammary gland, then Cav-1 null mice should show premature development of the lobuloalveolar compartment because of hyperactivation of the prolactin signaling cascade via disinhibition of Jak-2. In accordance with this prediction, Cav-1 null mice show accelerated development of the lobuloalveolar compartment, premature milk production, and hyperphosphorylation of STAT5a (pY694) at its Jak-2 phosphorylation site. In addition, the Ras-p42/44 MAPK cascade is hyper-activated. Because a similar premature lactation phenotype is observed in SOCS1 (-/-) null mice, we conclude that caveolin-1 is a novel suppressor of cytokine signaling.
Links	PubMed PMC129955 Online version:10.1091/mbc.02-05-0071
Keywords	Amino Acid Sequence; Animals; Carrier Proteins/genetics; Caveolin 1; Caveolins/genetics; Caveolins/metabolism; Cell Line; Cell Membrane/metabolism; DNA-Binding Proteins/metabolism; Down-Regulation/physiology; Enzyme Activation; Epithelial Cells/metabolism; Estrogens/metabolism; Female; Genes, Reporter; Janus Kinase 2; Lactation Disorders; Mammary Glands, Animal/cytology; Mammary Glands, Animal/growth & development; Mammary Glands, Animal/physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Milk Proteins/biosynthesis; Mitogen-Activated Protein Kinases/metabolism; Molecular Sequence Data; Pregnancy; Progesterone/metabolism; Prolactin/metabolism; Protein-Tyrosine Kinases/metabolism; Proteins/genetics; Proto-Oncogene Proteins; Repressor Proteins; STAT5 Transcription Factor; Sequence Alignment; Signal Transduction/physiology; Suppressor of Cytokine Signaling Proteins; Trans-Activators/metabolism; Transcription Factors
edit table

Annotations

Gene product	Qualifier	GO ID	GO term name	Evidence Code	with/from	Aspect	Notes	Status
edit table

References

See Help:References for how to manage references in GONUTS.