JAK2 activation and cell proliferation induced by antibody-mediated prolactin receptor dimerization.

Rui, Hallgeir; Lebrun, Jean Jacques; Kirken, Robert A.; Kelly, Paul A.; Farrar, William L.

doi:10.1210/endo.135.4.7925093

Cited by 137 publications

(80 citation statements)

References 31 publications

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“…Proteins were eluted from protein A-Sepharose beads, separated on SDS-PAGE (7.5% polyacrylamide), and transferred to polyvinylidene difluoride membranes. Labeled proteins were visualized by autoradiography and analyzed by phosphoamino acid analysis as described previously (29). Labeled Stat5a and Stat5b proteins were excised from polyvinylidene difluoride membranes and exposed to limited hydrolysis in 6 N HCl at 110°C for 90 min.…”

Section: Methodsmentioning

confidence: 99%

Two Discrete Regions of Interleukin-2 (IL2) Receptor β Independently Mediate IL2 Activation of a PD98059/Rapamycin/Wortmannin-insensitive Stat5a/b Serine Kinase

Kirken¹,

Malabarba²,

Xu³

et al. 1997

Journal of Biological Chemistry

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Many cytokines, hormones, and growth factors activate Janus kinases to tyrosine phosphorylate select members of the Stat transcription factors. For full transcriptional activation, Stat1 and Stat3 also require phosphorylation of a conserved serine residue within a mitogen-activated protein kinase phosphorylation consensus site. On the other hand, two recently identified and highly homologous Stat5a and Stat5b proteins lack this putative mitogen-activated protein kinase phosphorylation site. The present study set out to establish whether Stat5a and Stat5b are under the control of an interleukin-2 (IL2)-activated Stat5 serine kinase. We now report that IL2 stimulated marked phosphorylation of serine and tyrosine residues of both Stat5a and Stat5b in human T lymphocytes and in several IL2-responsive lymphocytic cell lines. No Stat5a/b phosphothreonine was detected. Phosphoamino acid analysis also revealed that Stat5a/b phosphotyrosine levels were maximized within 1-5 min of IL2 stimulation, whereas serine phosphorylation kinetics were slower. Interestingly, IL2-induced serine phosphorylation of Stat5a differed quantitatively and temporally from that of Stat5b with Stat5a serine phosphorylation leveling off after 10 min and the more pronounced Stat5b response continuing to rise for at least 60 min of IL2 stimulation. Furthermore, we identified two discrete domains of IL2 receptor ␤ (IL2R␤) that could independently restore the ability of a truncated IL2R␤ mutant to mediate Stat5a/b phosphorylation and DNA binding to the ␥-activated site of the ␤-casein gene promoter. These observations demonstrated that there is no strict requirement for one particular IL2R␤ region for Stat5 phosphorylation. Finally, we established that the IL2-activated Stat5a/b serine kinase is insensitive to several selective inhibitors of known IL2-stimulated kinases including MEK1/MEK2 (PD98059), mTOR (rapamycin), and phosphatidylinositol 3-kinase (wortmannin) as determined by phosphoamino acid and DNA binding analysis, thus suggesting that a yet-to-beidentified serine kinase mediates Stat5a/b activation.Interleukin-2 (IL2) 1 is a key regulator of normal immune function and acts on a variety of lymphoid cell types including T lymphocytes, B lymphocytes, and natural killer cells (1). IL2-induced effects are mediated by heterodimerization of two related transmembrane proteins of the hematopoietin receptor family that are designated IL2 receptor ␤-and ␥-chains (IL2R␤ and ILR2␥) (2-4). In addition to this pair of essential receptor subunits, a third non-conforming protein with a short cytoplasmic domain (TAC or IL2R␣) represents an accessory receptor subunit that can serve as a positive affinity modulator through its regulated expression (5-7). IL2-induced dimerization of IL2R␤ and IL2R␥ results in stimulation of the receptor-associated Janus kinases (JAK) JAK1 and/or JAK3 through intermolecular transphosphorylation (8, 9

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Section: Methodsmentioning

confidence: 99%

Two Discrete Regions of Interleukin-2 (IL2) Receptor β Independently Mediate IL2 Activation of a PD98059/Rapamycin/Wortmannin-insensitive Stat5a/b Serine Kinase

Kirken¹,

Malabarba²,

Xu³

et al. 1997

Journal of Biological Chemistry

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“…In ovine Stat5, Tyr-694 is phosphorylated in response to prolactin (36). Since prolactin activates Jak2 (42,43) and IL-2 instead activates Jak1 and Jak3 (11,18,19), we tested whether phosphorylation of the homologous tyrosines in human Stat5 (Tyr-694 for Stat5A and Tyr-699 for Stat5B) was required for IL-2 activation. Substitution of phenylalanines for tyrosines at these positions abrogated Stat5 activation.…”

Section: Isolation Of Two Closely Related Human Stat5 Cdnas Whosementioning

confidence: 99%

Cloning of Human Stat5B

Lin

Mietz

Modi

et al. 1996

Journal of Biological Chemistry

196

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We have isolated a second human Stat5 cDNA, Stat5B, and demonstrated that the genes encoding both Stat5A and Stat5B are located at chromosome 17q11.2. Both genes were constitutively transcribed in peripheral blood lymphocytes. By using specific antisera, we demonstrated that both Stat5A and Stat5B are activated by interleukin-2 (IL-2) in peripheral blood lymphocytes, natural killer-like YT leukemia cells, and human T cell lymphotropic virus type I-transformed MT-2 T cells. In COS-7 cells, which constitutively express the Janus family tyrosine kinase Jak1, reconstitution of IL-2-induced Stat5A and Stat5B DNA binding activities was dependent on the coexpression of Jak3 along with the IL-2 receptor ␤ chain and the common cytokine receptor ␥-chain. This IL-2-induced Stat5 activation was dependent on the presence of either of two tyrosines (Tyr-392 or Tyr-510) in the IL-2 receptor ␤ chain, indicating that either of these two tyrosines can serve as a docking site. Moreover, we demonstrated that human Stat5 activation is also dependent on Tyr-694 in Stat5A and Tyr-699 in Stat5B, indicating that these tyrosines are required for dimerization. The COS-7 reconstitution system described herein provides a valuable assay for further elucidation of the IL-2-activated JAK-STAT pathway.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Huang

Jiang

et al. 2006

Oncogene

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Prolactin (PRL) is a polypeptide hormone produced by the anterior pituitary gland and other sites that acts both systemically and locally to cause lactation and other biological effects by interacting with the PRL receptor, a Janus kinase (JAK)2-coupled cytokine receptor family member, and activating downstream signal pathways. Recent evidence suggests PRL is a player in the pathogenesis and progression of breast cancer. Epidermal growth factor (EGF) also has effects on breast tissue, working through its receptors, epidermal growth factor receptor (EGFR) and ErbB-2 (c-neu, HER2), both intrinsic tyrosine kinase growth factor receptors. EGFR promotes pubertal breast ductal morphogenesis in mice, and both EGFR and ErbB-2 are relevant in pathogenesis and behavior of breast and other human cancers. Previous studies showed that PRL and EGF synergize to enhance motility in the human breast cancer cell line, T47D. In this study, we explored crosstalk between the PRL and EGF signaling pathways in T47D cells, with an ultimate aim of understanding how these two important factors might work together in vivo to affect breast cancer behavior. Both PRL and EGF caused robust signaling in T47D cells; PRL acutely activated JAK2, signal transducer and activator of transcription-5 (STAT5), and extracellular signal-regulated kinase-1 and -2 (ERK1 and ERK2), whereas EGF caused EGFR activation and consequent src homology collagen (SHC) activation and ERK activation. Notably, PRL also caused phosphorylation of the EGFR and ErbB-2 at sites detected by PTP101, an antibody that recognizes threonine phosphorylation at consensus motifs for ERK-induced phosphorylation. PRL-induced PTP101-reactive phosphorylation was prevented by pretreatment with PD98059, an ERK pathway inhibitor. Furthermore, PRL synergized with EGF in activating SHC and ERK and transactivating a luciferase reporter driven by c-fos gene enhancer elements, suggesting that PRL allowed markedly enhanced EGF signaling. This was accompanied by substantial inhibition of EGF-induced EGFR downregulation when PRL and EGF cotreatment was compared to EGF treatment alone. This effect of PRL was abrogated by ERK pathway inhibitor pretreatment. Our data suggest that PRL synergistically augments EGF signaling in T47D breast cancer cells at least in part by lessening EGF-induced EGFR downregulation and that this effect requires PRL-induced ERK activity and threonine phosphorylation of EGFR.

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JAK2 activation and cell proliferation induced by antibody-mediated prolactin receptor dimerization.

Cited by 137 publications

References 31 publications

Two Discrete Regions of Interleukin-2 (IL2) Receptor β Independently Mediate IL2 Activation of a PD98059/Rapamycin/Wortmannin-insensitive Stat5a/b Serine Kinase

Two Discrete Regions of Interleukin-2 (IL2) Receptor β Independently Mediate IL2 Activation of a PD98059/Rapamycin/Wortmannin-insensitive Stat5a/b Serine Kinase

Cloning of Human Stat5B

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

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