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Published 5 June 2006. doi:10.1083/jcb.200601059
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 173, Number 5, 781-793
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Article

Rac1 links integrin-mediated adhesion to the control of lactational differentiation in mammary epithelia



Nasreen Akhtar and Charles H. Streuli

Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, England, United Kingdom

Correspondence to Charles Streuli: cstreuli{at}manchester.ac.uk

The expression of tissue-specific genes during mammary gland differentiation relies on the coincidence of two distinct signaling events: the continued engagement of ß1 integrins with the extracellular matrix (ECM) and a hormonal stimulus from prolactin (Prl). How the integrin and Prl receptor (PrlR) systems integrate to regulate milk protein gene synthesis is unknown. In this study, we identify Rac1 as a key link. Dominant-negative Rac1 prevents Prl-induced synthesis of the milk protein ß-casein in primary mammary epithelial cells cultured as three-dimensional acini on basement membrane. Conversely, activated Rac1 rescues the defective ß-casein synthesis that occurs under conditions not normally permissive for mammary differentiation, either in ß1 integrin–null cells or in wild-type cells cultured on collagen. Rac1 is required downstream of integrins for activation of the PrlR/Stat5 signaling cascade. Cdc42 is also necessary for milk protein synthesis but functions via a distinct mechanism to Rac1. This study identifies the integration of signals provided by ECM and hormones as a novel role for Rho family guanosine triphosphatases.

Abbreviations used in this paper: BM, basement membrane; DN, dominant negative; MEC, mammary epithelial cell; PAK, p21-activated protein kinase; PBD, PAK-binding domain; Prl, prolactin; PrlR, Prl receptor; PTP, protein tyrosine phosphatase.


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