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Published online 5 May 2003. doi:10.1083/jcb.200212066
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© The Rockefeller University Press, 0021-9525/2003/5/583 $5.00
The Journal of Cell Biology, Volume 161, Number 3, 583-592

Article

 Essential functions of p21-activated kinase 1 in morphogenesis and differentiation of mammary glands

Rui-An Wang1, Ratna K. Vadlamudi1, Rozita Bagheri-Yarmand1, Iwan Beuvink2, Nancy E. Hynes2 and Rakesh Kumar1

1 Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030
2 Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland

Address correspondence to Rakesh Kumar, M.D. Anderson Cancer Center-108, Rm. Y4.6032, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: (713) 745-3558. Fax: (713) 745-3792. E-mail: rkumar{at}mdanderson.org

Although growth factors have been shown to influence mammary gland development, the nature of downstream effectors remains elusive. In this study, we show that the expression of p21-activated kinase (Pak)1, a serine/threonine protein kinase, is activated in mammary glands during pregnancy and lactation. By targeting an ectopic expression of a kinase-dead Pak1 mutant under the control of ovine ß-lactoglobulin promoter, we found that the mammary glands of female mice expressing kinase-dead Pak1 transgene revealed incomplete lobuloalveolar development and impaired functional differentiation. The expression of whey acidic protein and ß-casein and the amount of activated Stat5 in the nuclei of epithelial cells in transgenic mice were drastically reduced. Further analysis of the underlying mechanisms revealed that Pak1 stimulated ß-casein promoter activity in normal mouse mammary epithelial cells and also cooperated with Stat5a. Pak1 directly interacted with and phosphorylated Stat5a at Ser 779, and both COOH-terminal deletion containing Ser 779 of Stat5a and the Ser 779 to Ala mutation completely prevented the ability of Pak1 to stimulate ß-casein promoter. Mammary glands expressing inactive Pak1 exhibited a reduction of Stat5a Ser 779 phosphorylation. These findings suggest that Pak1 is required for alveolar morphogenesis and lactation function, and thus, identify novel functions of Pak1 in the mammary gland development.

Key Words: mammary gland; morphogenesis; Pak1; Stat5; milk proteins

The online version of this article includes supplemental material.

* Abbreviations used in this paper: BLG, ß-lactoglobulin; DIP, dexamethasone, insulin, and prolactin; DN, dominant negative; H-E, hematoxylin and eosin; Pak1, p21-activated kinase; PCNA, proliferative cell nuclear antigen; WAP, whey acidic protein.


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