Figure 1.

Regulation of STAT signaling in mammary epithelial cells. Binding of prolactin (PRL) and placental lactogen (PL) to the PRLR or neuregulin1/neuregulin2 (NRG1/2) to ERBB4 activates the receptor-associated JAK kinase and induces the phosphorylation of STAT5A and STAT5B. Upon phosphorylation, STAT5 dimers translocate to the nucleus, where they bind to GAS elements and induce transcription of the genes encoding ELF5, SOCS1, SOCS2, and milk proteins. SOCS1/2 are recruited to the receptor and attenuate STAT5 signaling. Membrane-associated caveolin-1 modulates STAT5 activation by regulating JAK2 accessibility. The phosphatase SHP-2 regulates STAT5 phosphorylation by binding to the receptor and STAT5. ETS5 is a transcription factor in its own right that activates additional genes required for normal mammary function.