Figure 7

Model for the cell-type-specific role of Wip1 in the mammary gland. In the virgin state, Wip1 (also known as PPM1D; protein phosphatase magnesium-dependent 1D) is required to sensitize hormone-sensing cells (HS, red) to prolactin by promoting phosphorylation of signal transducer and activator of transcription 5 (STAT5), whereas STAT5 activation is undetectable in adjacent alveolar progenitor cells (Alv, purple), even when Wip1 is expressed. During pregnancy, prolactin levels increase, and STAT5 is activated in both hormone-sensing and alveolar progenitor cells (blue arrows), independent of Wip1. In the absence of Wip1, STAT5-induced transcription of β-casein in alveolar cells is unaffected, but in hormone-sensing cells, transcription of paracrine regulators RANKL (receptor activator of nuclear factor kappa-B ligand) and IGF2 (insulin-like growth factor-2) is significantly reduced. In the context of HER2/neu (human epidermal growth factor receptor 2) activation, STAT5 is phosphorylated in alveolar progenitor cells independent of Wip1, but Wip1 is required for both STAT5 and ERK (extracellular signal-regulated kinase) activation in hormone-sensing cells. Thus, Wip1 potentiates prolactin and HER2/neu signaling specifically in hormone-sensing cells and is important for the production of paracrine stimulators of alveolar development.