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Coactivation of Janus Tyrosine Kinase (Jak)1 Positively Modulates Prolactin-Jak2 Signaling in Breast Cancer: Recruitment of ERK and Signal Transducer and Activator of Transcription (Stat)3 and Enhancement of Akt and Stat5a/b Pathways

Kimmel Cancer Center (L.M.N., J.Z., J.X., H.R.), Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; Tumor Biology Graduate Program (L.M.N.), Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, D.C. 20057; IFOM (M.G.M.), the FIRC Institute for Molecular Oncology Foundation, 20139 Milan, Italy; Dipartimento di Medicina (M.G.M.), Chirurgia ed Odontoiatria, Università degli Stadi di Milano, 20122 Milan, Italy; Eppley Institute for Research in Cancer and Allied Diseases and the Department of Pathology and Microbiology (K.S., K.-U.W.), University of Nebraska Medical Center, Omaha, Nebraska 68198; and Department of Biological Sciences (R.A.K.), University of Texas, El Paso, Texas 79968

Address all correspondence and requests for reprints to: Hallgeir Rui, Department of Cancer Biology, Thomas Jefferson University, 233 South Tenth Street, BLSB 330, Philadelphia, Pennsylvania 19107. E-mail: Hallgeir.Rui{at}jefferson.edu.

Prolactin (PRL) receptors (PRLRs) have been considered selective activators of Janus tyrosine kinase (Jak)2 but not Jak1, Jak3, or Tyk2. We now report marked PRL-induced tyrosine phosphorylation of Jak1, in addition to Jak2, in a series of human breast cancer cell lines, including T47D, MCF7, and SKBR3. In contrast, PRL did not activate Jak1 in immortalized, noncancerous breast epithelial lines HC11, MCF10A, ME16C, and HBL-100, or in CWR22Rv1 prostate cancer cells or MDA-MB-231 breast cancer cells. However, introduction of exogenous PRLR into MCF10A, ME16C, or MDA-MB-231 cells reconstituted both PRL-Jak1 and PRL-Jak2 signals. In vitro kinase assays verified that PRL stimulated enzymatic activity of Jak1 in T47D cells, and PRL activated Jak1 and Jak2 with indistinguishable time and dose kinetics. Relative Jak2 deficiency did not cause PRLR activation of Jak1, because overexpression of Jak2 did not interfere with PRL activation of Jak1. Instead, PRL activated Jak1 through a Jak2-dependent mechanism, based on disruption of PRL activation of Jak1 after Jak2 suppression by 1) lentiviral delivery of Jak2 short hairpin RNA, 2) adenoviral delivery of dominant-negative Jak2, and 3) AG490 pharmacological inhibition. Finally, suppression of Jak1 by lentiviral delivery of Jak1 short hairpin RNA blocked PRL activation of ERK and signal transducer and activator of transcription (Stat)3 and suppressed PRL activation of Jak2, Stat5a, Stat5b, and Akt, as well as tyrosine phosphorylation of PRLR. The data suggest that PRL activation of Jak1 represents a novel, Jak2-dependent mechanism that may serve as a regulatory switch leading to PRL activation of ERK and Stat3 pathways, while also serving to enhance PRL-induced Stat5a/b and Akt signaling.