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Vol. 13, Issue 10, 3416-3430, October 2002

Caveolin-1-deficient Mice Show Accelerated Mammary Gland Development During Pregnancy, Premature Lactation, and Hyperactivation of the Jak-2/STAT5a Signaling Cascade

David S. Park,*dagger Hyangkyu Lee,*dagger Philippe G. Frank,*dagger Babak Razani,*dagger Andrew V. Nguyen,Dagger Albert F. Parlow,§ Robert G. Russell,|| James Hulit,dagger Richard G. Pestell,dagger and Michael P. Lisanti*dagger #

 *Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461;  dagger Division of Hormone-dependent Tumor Biology, The Albert Einstein Cancer Center, Bronx, NY 10461;  Dagger 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

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.

# Corresponding author. E-mail address: lisanti{at}aecom.yu.edu.

Molecular Biology of the Cell
Vol. 13, 3416-3430, October 2002
Copyright © 2002 by The American Society for Cell Biology


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