Stimulation of c-Src by prolactin is independent of Jak2

Vara, Juan Ángel Fresno; Carretero, María; Gerónimo, Haydeé; Ballmer-Hofer, Kurt; Martı́n-Pérez, Jorge

doi:10.1042/0264-6021:3450017

Cited by 41 publications

(13 citation statements)

References 50 publications

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“…Surprisingly, the molecular analysis of JAK2 deficient mammary epithelial cells revealed that the SRC tyrosine kinase, the focal adhesion kinase (FAK), and MAP kinases could still be effectively activated in response to PRL stimulation (Sakamoto et al, 2007). This finding supports previous observations by Fresno Vara and colleagues (2000) that the PRLR-mediated activation of the c-SRC kinase occurs independently of JAK2 in human breast cancer cells. Since JAK2 deficient mammary epithelial cells lack active STAT5, it is evident that SRC does not activate STAT5 directly in a JAK2-independent manner.…”

Section: Evidence For a Crosstalk Between Active Stat5 And Pi3k/akt Isupporting

confidence: 93%

Crosstalk between STAT5 activation and PI3K/AKT functions in normal and transformed mammary epithelial cells

Rädler

Wehde

Wagner

2017

Molecular and Cellular Endocrinology

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Summary Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) have been shown to function downstream of several peptide hormones and cytokines that are required for postnatal development and secretory function of the mammary gland. As part of an extended network, these signal transducers can engage in crosstalk with other pathways to facilitate synergistic, and sometimes antagonistic, actions of different growth factors. Specifically, signaling through the JAK2/STAT5 cascade has been demonstrated to be indispensable for the specification, proliferation, differentiation, and survival of secretory mammary epithelial cells. Following a concise description of major cellular programs in mammary gland development and the role of growth factors that rely on JAK/STAT signaling to orchestrate these programs, this review highlights the significance of active STAT5 and its crosstalk with the PI3 kinase and AKT1 for mediating the proliferation of alveolar progenitors and survival of their functionally differentiated descendants in the mammary gland. Based on its ability to provide self-sufficiency in growth signals that are also capable of overriding intrinsic cell death programs, persistently active STAT5 can serve as a potent oncoprotein that contributes to the genesis of breast cancer. Recent experimental evidence demonstrated that, similar to normal developmental programs, oncogenic functions of STAT5 rely on molecular crosstalk with PI3K/AKT signaling for the initiation, and in some instances the progression, of breast cancer. The multitude by which STATs can interact with individual mediators of the PI3K/AKT signaling cascade may provide novel avenues for targeting signaling nodes within molecular networks that are crucial for the survival of cancer cells.

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Section: Evidence For a Crosstalk Between Active Stat5 And Pi3k/akt Isupporting

confidence: 93%

Crosstalk between STAT5 activation and PI3K/AKT functions in normal and transformed mammary epithelial cells

Rädler

Wehde

Wagner

2017

Molecular and Cellular Endocrinology

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“…Previous studies have shown that Src‐kinase is activated by different cytokines 63. Src kinase has been shown to be stimulated by the prolactin receptor, which belongs to the class I cytokine receptor family, independently of JAK2 42. Similar results have been shown for growth hormone 64.…”

Section: Discussionsupporting

confidence: 66%

“…Src kinase is activated by the class I cytokine receptor family, as shown for the prolactin receptor,42 and is involved in the regulation of cell motility 43. We used a specific Src kinase inhibitor‐Src kinase inhibitor II (SrcKI‐II), to investigate whether Src kinase is involved in leptin stimulation of Rho GTPase activity.…”

Section: Resultsmentioning

confidence: 99%

Leptin promotes motility and invasiveness in human colon cancer cells by activating multiple signal‐transduction pathways

Jaffe

Schwartz

2008

Intl Journal of Cancer

119

103

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Leptin serum levels are about 5 times higher in obese people than in normal individuals. We aimed at investigating the signaling pathways induced by leptin in the human colonic cell lines LS174T and HM7. Both cells expressed the leptin transmembrane Ob-receptor. Leptin activated the mitogen-activated protein kinase pathway, induced invasion of colonic cells and concomitantly increased the formation of lamellipodial structures. A direct and novel dose-and time-dependent activation of RhoA, Cdc42 and Rac1 by leptin is demonstrated in these aggressive colon cancer cells. The activation of the Rho family of GTPases was amenable to specific inhibition: Wortmannin inhibited leptin-induced Rac1 and Cdc42 activation but did not affect RhoA activation, and inhibited the formation of leptin-induced lamellipodia and cell invasion. The Rac1 inhibitor NSC23766 inhibited only leptininduced Rac1 activation and concomitantly, lamellipodium formation and cell invasion. The Src kinase inhibitor II (SrcKI-II) exerted a positive effect on RhoA activation, inhibited tyrosine phosphorylation of p190RhoGAP and inhibited leptin-induced Cdc42 activation and leptin-induced lamellopodium formation and cell invasion. The specific JAK2 inhibitor AG490 exerted a positive effect on Rac1 and Cdc42 activation by leptin and concomitantly inhibited RhoA activation. AG490 did not inhibit leptin-induced lamellopodium formation or cell invasion. Our findings clearly indicate that leptin activates PI3K and Src kinase pathways in the metastatic colon cancer cells LS174T and HM7. These signaling pathways induce the activation of Rac1 and Cdc42, lamellopodium formation and concomitantly enhanced cell invasion, but leptin activation of RhoA is not associated with enhanced cell locomotion and invasion. Understanding in-depth the pathways involved in leptin-associated enhanced cell locomotion and invasion may contribute with the design of novel therapeutics to treat obesity-associated advanced colorectal cancer.

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“…Activated Stats dimerize, translocate into the nucleus, and bind to specific sequences on target genes [123]. The Src family kinases and the ras/raf/mitogen-activated protein kinase (MAPK) cascade are also activated by PRL [124], directly stimulating proliferation and modulating Stat activity [125]; however, they appear to be less important than the Jak-Stat pathway for transducing the effects of PRL.…”

Section: Prl and Gh Signaling Pathwaysmentioning

confidence: 98%

Vitamin D, Pit-1, GH, and PRL: Possible Roles in Breast Cancer Development

Perez-Fernandez

Seoane²,

García‐Caballero³

et al. 2007

CMC

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1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the most active metabolite of vitamin D, exerts its biological effects by binding to a specific intracellular receptor (the vitamin D receptor, VDR) present in target cells. 1,25-(OH)(2)D(3) is involved in a host of cell processes, including calcium homeostasis, cell growth and differentiation, and secretion of hormones. Several studies have explored the role of 1,25-(OH)(2)D(3) in cell growth and differentiation in normal and tumoral mammary gland, in which it shows antiproliferative effects. These effects have been attributed to suppression of growth-stimulatory signals and potentiation of growth-inhibitory signals, leading to changes in cell-cycle regulators as well as to induction of apoptosis. In apparent contrast to these antiproliferative effects, however, several studies have suggested that breast tumor formation may be related to the autocrine/paracrine effects of growth hormone (GH) and prolactin (PRL). The pituitary transcription factor-1 (Pit-1), which in the pituitary is critical to both cell differentiation and PRL and GH transcription, has been recently found in normal and tumoral human breast tissue, with mRNA expression levels significantly higher in tumors than in normal breast. As in the pituitary, Pit-1 regulates mammary GH and PRL secretion, increases cell proliferation and decreases apoptosis. 1,25-(OH)(2)D(3) administration to the MCF-7 human breast adenocarcinoma cell line significantly reduces Pit-1 expression, suggesting that inhibition of Pit-1 expression by 1,25-(OH)(2)D(3) may reduce the increase in proliferation induced by this transcription factor directly or indirectly through increased GH and/or PRL expression. In this review, we evaluate the role of 1,25-(OH)(2)D(3) and Pit-1/PRL/GH in human breast, and consider the relationships between these factors in normal mammary development and in breast cancer.

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Stimulation of c-Src by prolactin is independent of Jak2

Cited by 41 publications

References 50 publications

Crosstalk between STAT5 activation and PI3K/AKT functions in normal and transformed mammary epithelial cells

Crosstalk between STAT5 activation and PI3K/AKT functions in normal and transformed mammary epithelial cells

Leptin promotes motility and invasiveness in human colon cancer cells by activating multiple signal‐transduction pathways

Vitamin D, Pit-1, GH, and PRL: Possible Roles in Breast Cancer Development

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