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Vol. 13, Issue 10, 3416-3430, October 2002
¶¶ and#
*Department of Molecular Pharmacology, Albert Einstein College of
Medicine, Bronx, NY 10461; 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 (Division of Hormone-dependent
Tumor Biology, The Albert Einstein Cancer Center, Bronx, NY 10461;
Department of Microbiology and Immunology, Albert
Einstein College of Medicine, Bronx, NY 10461; §National
Hormone and Pituitary Program, Harbor-UCLA Medical Center Research and
Education Institute, Torrance, CA 90509; Department of
Pathology and The Institute for Animal Studies, Albert Einstein College
of Medicine, Bronx, NY 10461; and ¶Departments of
Developmental and Molecular Biology (DMB) and Medicine, Albert Einstein
College of Medicine, Bronx, NY 10461
/) 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.
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