Caveolin-1-deficient mice show accelerated mammary gland development during pregnancy, premature lactation, and hyperactivation of the Jak-2/STAT5a signaling cascade.
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.
Mesh Terms:
Amino Acid Sequence, Animals, Carrier Proteins, Caveolin 1, Caveolins, Cell Line, Cell Membrane, DNA-Binding Proteins, Down-Regulation, Enzyme Activation, Epithelial Cells, Estrogens, Female, Genes, Reporter, Janus Kinase 2, Lactation Disorders, Mammary Glands, Animal, Mice, Mice, Inbred C57BL, Mice, Knockout, Milk Proteins, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Pregnancy, Progesterone, Prolactin, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Repressor Proteins, STAT5 Transcription Factor, Sequence Alignment, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Trans-Activators, Transcription Factors
Amino Acid Sequence, Animals, Carrier Proteins, Caveolin 1, Caveolins, Cell Line, Cell Membrane, DNA-Binding Proteins, Down-Regulation, Enzyme Activation, Epithelial Cells, Estrogens, Female, Genes, Reporter, Janus Kinase 2, Lactation Disorders, Mammary Glands, Animal, Mice, Mice, Inbred C57BL, Mice, Knockout, Milk Proteins, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Pregnancy, Progesterone, Prolactin, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Repressor Proteins, STAT5 Transcription Factor, Sequence Alignment, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Trans-Activators, Transcription Factors
Mol. Biol. Cell
Date: Oct. 01, 2002
PubMed ID: 12388746
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