Fig. 4.

Aspects of PRLR signaling as related to mammary gland function. Relationships between some of the salient PRLR-associated transduction cascades are demonstrated. PRL-induced receptor dimerization induces the association of the Jak2 kinase, resulting in the activation of Jak2, PRLR phosphorylation, and the association and phosphorylation of Stat5. This triggers Stat5 dimerization and nuclear translocation and events necessary for PRL-triggered mammary differentiation. Signaling through the SHC/GRB2/Ras/Raf/MEK/MAPK pathway also directly stimulates proliferation and modulates Stat activity. Furthermore, the complex between the Tec tyrosine kinase and the Vav family of guanine nucleotide exchange factors also inducibly associates with ligand-bound PRLR. This results in the exchange of GDP for GTP on the small G protein Rac, resulting in its activation and stimulation of cellular motility. Activation of Tec and the kinase Akt are directly tied to the PRL-induced activation of PI3K. The phosphatase SHP-2 also associates with the PRLR and potentiates its activity.