Both the transforming growth factor- (TGF)/Smad and the prolactin/JAK/STAT pathway are critical to the proper development, maintenance, and function of the mammary epithelial tissue. Interestingly, opposing physiological effects between these two signaling pathways are prominent in the regulation of mammary gland development. However, the exact nature of the biological network existing between the Smad and STAT signal transduction pathways has remained elusive. We identified a novel regulatory cross-talk mechanism by which TGF-induced Smad signaling acts to antagonize prolactin-mediated JAK/ STAT signaling and expression of target genes. Furthermore, we found activin, another member of the TGF family, to also efficiently block STAT5 signaling and -casein expression in mammary epithelial cells. Our results indicate that ligand-induced activation of Smad2, -3, and -4 by activin and TGF leads to a direct inhibition of STAT5 transactivation and STAT5-mediated transcription of the downstream target genes, -casein and cyclin D1, thereby blocking vital processes for mammary gland growth and differentiation. Finally, we unveiled the mechanism by which these two signaling cascades antagonize their effects, and we found that activated Smads inhibit STAT5 association with its co-activator CREB-binding protein, thus blocking STAT5 transactivation of its target genes and leading to inhibition of mammary gland differentiation and lactation.Mammary gland growth and differentiation are complex processes regulated by steroids, polypeptide hormones, and growth factors. Among them, prolactin and TGF 5 family members play a major role in the regulation of mammary gland development. Prolactin is required for lobuloalveolar formation and functional differentiation of mammary epithelial cells.TGF has an opposite effect, inducing apoptosis during mammary gland involution and inhibiting expression of the milk proteins (1, 2). TGF is expressed and plays critical roles in every phase of post-natal mammary gland development (3). TGF has been shown to inhibit alveolar formation and synthesis of milk proteins and to induce apoptosis during involution of the mammary gland (4 -6). Together, these data suggest that TGF would antagonize prolactin (PRL)-induced signals in mammary cells (7,8). The effect of activin, another member of the TGF family, on the development of the mammary gland stems from the activin b subunit knock-out mouse model. Deletion of the activin b subunit, through ablation of three of the dimeric  molecules (activin B, activin AB, and inhibin B), results in mice with the phenotype of incomplete mammary development and an absence of lactation, suggesting that activin/inhibin may play an important role in this process (9). In summary, although TGF and activin clearly play important roles in mammary gland development, their mechanism of action in mammary epithelial functional differentiation has yet to be fully elucidated.Prolactin signal transduction is induced by formation of a homodimeric complex of two molec...
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