Activation of JAK2 tyrosine kinase by prolactin receptors in Nb2 cells and mouse mammary gland explants.

Abstract

One of the earliest cellular responses to prolactin (PRL) binding in Nb2 cells, a rat pre-T lymphoma cell line, is an increase in tyrosine phosphorylation of cellular proteins. In this work, immunologic techniques have been used to demonstrate that in Nb2 cells and in mouse mammary gland explants, JAK2, a non-receptor tyrosine kinase, is activated following stimulation with PRL. PRL stimulated tyrosine phosphorylation of JAK2 at times as early as 30 sec and concentrations of PRL as low as 0.5 ng/ml (2.5 pM) in Nb2 cells and 100 ng/ml (5 nM) in mammary gland explants. When JAK2 was immunoprecipitated from solubilized Nb2 cells or mamMary gland explants and incubated with [r32P]ATP, 32P was incorporated into a protein mirating with an apparent molecular weight appropriate for JAK2 only when cells had been incubated with PRL, indicating that JAK2 tyrosine kinase activity is exquisitely sensitive to PRL. In Nb2 cells, JAK2 was found to associate with PRL receptor irrespective ofwhether or not the cells had been incubated with PRL. These results provide strong evidence that JAK2 is constitutively asiated with the PRL receptor and that it is activated and tyrosine phosphorylated upon PRL binding to the PRL receptor. These results are consistent with JAK2 serving as an early, perhaps initial, sgnaling molecule for PRL.

Colony‐stimulating factors and interferon‐γ activate a protein related to MGF‐Stat 5 to cause formation of the differentiation‐induced factor in myeloid cells

“…The prolactin receptor activates Jak 2 in vivo [29][30][31][32]. GM-CSF and IFN-y receptors are both capable of activating Jak2 [33][34][35].…”

Activation of the unliganded estrogen receptor by prolactin in breast cancer cells

“…In breast cancer cell lines PRL stimulates both the JAK1 and JAK2 pathways (Campbell et al, 1994;Liu et al, 1997;Neilson et al, 2007), and we have previously demonstrated that PRL stimulates Src kinases, which then independently activate Fak/ERK1/2 and the PI3K-dependent p70S6K and Akt kinases (Acosta et al, 2003). Activated ERK1/2 and AKT lead among others to increased AP-1 complexes, and induce the expression of cell-cycle progression genes such as cyclin D1 or c-myc (Brockman et al, 2002;Acosta et al, 2003;Gutzman et al, 2005).…”

Prolactin modulates phosphorylation, signaling and trafficking of epidermal growth factor receptor in human T47D breast cancer cells

“…Although controversial, the contribution of PRL to the pathogenesis and progression of human breast cancer is increasingly appreciated (Hankinson et al, 1999;Vonderhaar, 1999;Llovera et al, 2000b;Ben-Jonathan et al, 2002;Clevenger et al, 2003). PRL signals via the PRL receptor (PRLR), a cytokine receptor family member, which possesses no intrinsic tyrosine kinase activity and couples to the nonreceptor tyrosine kinase, Janus kinase (JAK)2 (Bazan, 1990;Argetsinger et al, 1993;Campbell et al, 1994;Rui et al, 1994;Bole-Feysot et al, 1998). Among other pathways, PRL activates the extracellular signal-regulated kinase (ERK) and STAT signaling pathways, with STAT5a being the principal STAT isoform involved in its mammary effects (Campbell et al, 1994;Rui et al, 1994;Liu et al, 1997;Clevenger and Kline, 2001).…”

“…PRL signals via the PRL receptor (PRLR), a cytokine receptor family member, which possesses no intrinsic tyrosine kinase activity and couples to the nonreceptor tyrosine kinase, Janus kinase (JAK)2 (Bazan, 1990;Argetsinger et al, 1993;Campbell et al, 1994;Rui et al, 1994;Bole-Feysot et al, 1998). Among other pathways, PRL activates the extracellular signal-regulated kinase (ERK) and STAT signaling pathways, with STAT5a being the principal STAT isoform involved in its mammary effects (Campbell et al, 1994;Rui et al, 1994;Liu et al, 1997;Clevenger and Kline, 2001). PRL induces ERK activity in several breast cancer cell lines, which may be important in PRL-induced biological effects in these cells (Das and Vonderhaar, 1996a, b;Llovera et al, 2000a;Schroeder et al, 2002;Acosta et al, 2003).…”