Abstract
Janus kinase 2 (JAK2) and signal transducers and activators of transcription 5 (STAT5) are involved in the proliferation, differentiation, and survival of mammary gland epithelial cells. Dysregulation of JAK2-STAT5 activity invariably leads to mammary gland developmental defects and/or diseases, including breast cancer. Proper functioning of the JAK2-STAT5 signaling pathway relies on crosstalk with other signaling pathways (synergistically or antagonistically), which leads to normal biological performance. This review highlights recent progress regarding the critical components of the JAK2-STAT5 pathway and its crosstalk with G-protein coupled receptor (GPCR) signaling, PI3K-Akt signaling, growth factors, inflammatory cytokines, hormone receptors, and cell adhesion.
Highlights
The mammary gland is a critical organ in mammals and is involved in milk production and delivery
Signal transducers and activators of transcription 5 is a crucial transcription factor that directly regulates multiple genes that participate in proliferation, differentiation, and milk secretion in the mammary gland
The current understanding of the crosstalk between Janus kinase 2 (JAK2)-signal transducers and activators of transcription 5 (STAT5) and other signals includes the following: (1) activation of the Gαi or Gαq G-protein coupled receptor (GPCR) signaling pathway is thought to increase the phosphorylation of STAT5, and the effects of different types of GPCRs could be different due to the bias of agonists; (2) Akt1 activates STAT5 phosphorylation, which can increase the expression of Akt1 and phosphatidylinositol 3-kinase (PI3K) subunits (p85α and p110α); (3) TGFβ, TNF-α, IL-6, and IL-1β are negative regulators of STAT5 activation, while the effects of Epidermal growth factor (EGF) on the mammary gland are still controversial; (4) estrogen receptors (ERs), GR and PR are positive regulators of the JAK2-STAT5 signaling pathway by directly interacting with the DNA domain; and (5) cell adhesion is crucial in maintaining the PrlR/STAT5 signaling cascade through β1-integrin
Summary
The mammary gland is a critical organ in mammals and is involved in milk production and delivery. The development of the embryonic mammary gland starts with the formation of placodes, which invaginate the mesenchyme and form mammary gland buds (Robinson, 2008). The second stage of mammary gland development is initiated at puberty During this period, mammary gland development is regulated and sustained by hormones, growth factors and cytokines. The mature mammary duct is mainly composed of myoepithelial cells (outer layer) and luminal epithelial cells (inner layer) During gestation, these mammary epithelial cells differentiate into milk-producing secretory alveoli, which synthesize the majority of milk fat, protein and lactose (Brisken et al, 1999; Oakes et al, 2008). JAK2-STAT5 is proposed to be a critical signaling pathway in the mammary gland. We focus on the constitutive and extensive communication between JAK2-STAT5 and other signaling pathways
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