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.
Park
David S
DS
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Lee
Hyangkyu
H
Frank
Philippe G
PG
Razani
Babak
B
Nguyen
Andrew V
AV
Parlow
Albert F
AF
Russell
Robert G
RG
Hulit
James
J
Pestell
Richard G
RG
Lisanti
Michael P
MP
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D051242:Caveolin 1; D022461:Caveolins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D017930:Genes, Reporter; D053614:Janus Kinase 2; D007775:Lactation Disorders; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors
D002352:Carrier Proteins; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D004268:DNA-Binding Proteins; D004967:Estrogens; D008894:Milk Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; C494093:Stat5a protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D011374:Progesterone; D011388:Prolactin; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases