A role for the cytoskeleton in prolactin-dependent mammary epithelial cell differentiation

Abstract

The function of exocrine glands depends on signals within the extracellular environment. In the mammary gland, integrin-mediated adhesion to the extracellular matrix protein laminin co-operates with soluble factors such as prolactin to regulate tissue-specific gene expression. The mechanism of matrix and prolactin crosstalk and the activation of downstream signals are not fully understood. Because integrins organize the cytoskeleton, we analysed the contribution of the cytoskeleton to prolactin receptor activation and the resultant stimulation of milk protein gene expression. We show that the proximal signalling events initiated by prolactin (i.e. tyrosine phosphorylation of receptor and the associated kinase Jak2) do not depend on an intact actin cytoskeleton. However, actin networks and microtubules are both necessary for continued mammary cell differentiation, because cytoskeletal integrity is required to transduce the signals between prolactin receptor and Stat5, a transcription factor necessary for milk protein gene transcription. The two different cytoskeletal scaffolds regulate prolactin signalling through separate mechanisms that are specific to cellular differentiation but do not affect the general profile of protein synthesis.

Membrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL-7 Receptor Signalosome in Human CD4 T-cells

“…Induction of cytoskeleton structuring has been described with many cytokines and chemokines but mostly over longer time spans. Pioneering studies on prolactin receptor (35), growth hormone receptor (36), and epidermal growth factor receptor (37) have suggested that machineries carried by the cytoskeleton might be involved in STAT5 and pSTAT5 distribution and proposed that rapid organization was involved. Here, in our study, we used super-resolution optical microscopy to describe in detail how radial microtubules are formed within a few min of IL-7 activation, bridging plasma and nuclear membranes across the narrow cytoplasm of CD4 T-lymphocytes.…”

Local over-expression of prolactin in differentiating mouse mammary gland induces functional defects and benign lesions, but no carcinoma

“…However, based on very similar phenotypes, Rac3 appears to be a good candidate to be considered. Connections between PRL, extracellular matrix proteins, and cytoskeleton play a critical role in maintaining mammary cell adhesion, morphology and function (Edwards et al 1998, Zoubiane et al 2004. b-catenin is a multifunctional protein connecting cytoskeleton proteins, and it plays a critical role in Wnt signaling in the mammary gland (Muller et al 2002).…”

Regulation of Mammary Development as It Relates to Changes in Milk Production Efficiency

“…In no culture conditions has there been any significant expression of -lactalbumin (and, consequently, there is no synthesis of lactose), indicating that expression of this protein is regulated by an alternative mechanism within the mammary gland (Lee et al, 1984;Wilde et al, 1984;Bissell & Hall, 1987). More recently, it has been observed that in addition to the presence of ECM, adhesion of the mammary epithelium to ECM is critical for cellular differentiation (Zoubiane et al, 2004). Based on their observations, these authors suggested a role for the integrins in coordinating the cytoskeleton and regulating the induction of cellular differentiation by PRL.…”