Jaks and Stats in signaling by the cytokine receptor superfamily

Overexpression of the oncogene for ErbB-2 is an unfavorable prognostic marker in human breast cancer.Its oncogenic potential appears to depend on the state of tyrosine phosphorylation. However, the mechanisms by which ErbB-2 is constitutively tyrosine-phosphorylated in human breast cancer are poorly understood. We now show that human breast carcinoma samples with ErbB-2 overexpression have higher proliferative and metastatic activity in the presence of autocrine secretion of prolactin (PRL). By using a neutralizing antibody or dominant negative (DN) strategies or specific inhibitors, we also show that activation of Janus kinase Jak2 by autocrine secretion of PRL is one of the significant components of constitutive tyrosine phosphorylation of ErbB-2, its association with Grb2 and activation of mitogen-activated protein (MAP) kinase in human breast cancer cell lines that overexpress ErbB-2. Furthermore, the neutralizing anti-PRL antibody or erbB-2 antisense oligonucleotide or DN Jak2 or Jak2 inhibitor or DNRas or MAP kinase kinase inhibitor inhibits the proliferation of both untreated and PRL-treated cells. Our results indicate that autocrine secretion of PRL stimulates tyrosine phosphorylation of ErbB-2 by Jak2, provides docking sites for Grb2 and stimulates Ras-MAP kinase cascade, thereby causing unrestricted cellular proliferation. The identification of this novel cross-talk between ErbB-2 and the autocrine growth stimulatory loop for PRL may provide new targets for therapeutic and preventive intervention of human breast cancer.

Section: Breast Cancer Affects One In Every Eight Women In the Unitedmentioning

confidence: 99%

Constitutive Tyrosine Phosphorylation of ErbB-2 via Jak2 by Autocrine Secretion of Prolactin in Human Breast Cancer

Yamauchi¹,

Yamauchi²,

Ueki³

et al. 2000

“…The Jak tyrosine kinases function upstream of the STAT family of transcription factors (35,36). A recent report showed that STAT3 associates with p85 and links it to the interferon-␥ receptor (76).…”

Section: Figmentioning

confidence: 99%

“…The Jak family functions upstream of a family of transcription factors called STATs (signal transducers and activators of transcription) (35,36). Eight different STATs have been identified so far (STAT1 ␣ and ␤, STAT2-4, STAT5A and B, and STAT6).…”

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confidence: 99%

“…The STATs are activated by tyrosine phosphorylation (37) and in some cases by an additional serine phosphorylation (38). The phosphorylated STATs will form homo-as well as heterodimers and migrate to the nucleus where they bind specific DNA motifs (35,36,39). Which members of the Jak and STAT family are activated varies greatly among different agonists and for the same agonist but in different cell systems (29, 40 -43).…”

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confidence: 99%

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Granulocyte-Macrophage Colony-stimulating Factor-activated Signaling Pathways in Human Neutrophils

Al-Shami

Naccache

1999

Granulocyte-macrophage colony-stimulating factor (GM-CSF) regulates many of the biological activities of human neutrophils. The signaling pathways via which these effects are mediated are not fully understood. We have shown previously that GM-CSF treatment of human neutrophils activates the Janus kinase/signal transducers and activators of transcription (Jak/STAT) pathway and, more specifically, Jak2, STAT3, and STAT5B in neutrophils. GM-CSF also stimulates the activity of the phosphatidylinositol 3-kinase (PI3-kinase) in a tyrosine kinase-dependent manner. Here we report that pretreating the cells with a Jak2 inhibitor (AG-490) abolishes tyrosine phosphorylation of the p85 subunit of PI3-kinase induced by GM-CSF. Furthermore, p85 was found to associate with Jak2, but not with Lyn, in stimulated cells in situ and with its autophosphorylated form in vitro; however, Jak2 did not bind to either of the two Src homology 2 (SH2) domains of the p85 subunit of PI3-kinase. Although STAT5B bound to the carboxylterminal SH2 domain of p85, it was absent from the complex containing PI3-kinase and Jak2. These results suggest that stimulation of the activity of PI3-kinase induced by GM-CSF is mediated by Jak2 and that the association between Jak2 and p85 depends on an adaptor protein yet to be identified.

“…A role for the JAKs in the recruitment/ activation of additional signaling molecules is, however, less well established. Mutant human fibrosarcoma cell lines lacking individual JAKs, originally isolated as being defective in signal transduction in response to the IFNs (40 -42), have been used widely in the analysis of JAK/STAT pathways in response to a variety of ligands (17,18,43). Here they have been used, together with murine 32D cells that lack IRS-1 and IRS-2, to determine the JAK dependence of IRS protein phosphorylation in response to IL-4, OSM, and the IFNs and to analyze the IRS protein dependence of the IFN response.…”

mentioning

confidence: 99%

Janus Kinase-dependent Activation of Insulin Receptor Substrate 1 in Response to Interleukin-4, Oncostatin M, and the Interferons

Burfoot

Rogers

Watling

et al. 1997

Self Cite

114

In addition to a role in response to insulin and insulinlike growth factors, insulin receptor substrate 1 (IRS-1) is phosphorylated in response to IL-4, the interferons (IFNs) and oncostatin M (OSM). Here mutant cell lines lacking JAK1, JAK2, or Tyk2 were used to determine the role(s) of the Janus kinase (JAK) family of protein-tyrosine kinases in IRS-1 phophorylation. 32D cells, which do not express IRS proteins, were analyzed for any requirement for these proteins in response to the IFNs. For the mutant human fibrosarcoma cell lines, phosphorylation of IRS-1 through the insulin-like growth factor receptor is independent of JAK1, JAK2, or Tyk2. In contrast, phosphorylation of IRS-1 mediated by the Type I IFNs, IL-4, and OSM is JAK-dependent. For the ␣␤-IFNs, activation of IRS-1 is dependent on JAK1 and Tyk2, consistent with the interdependence of these kinases in the IFN-␣␤ response. Neither IRS-1 nor IRS-2 was detectably activated by IFN-␥. Consistent with this, activation of neither IRS proteins appears to be an absolute requirement for an antiproliferative or an antiviral response to the IFNs. For IL-4 and OSM phosphorylation of IRS-1 in the human fibrosarcoma cells is largely dependent on JAK1 but can also be mediated through Tyk2 or JAK2. Activation of phosphatidylinositol 3 -kinase in response to IL-4 and OSM, at least, was also JAK-dependent. The JAKs are, therefore, required not only for STAT activation but also for the activation, through a variety of different types of cytokine receptor, of an additional signaling pathway(s) through IRS-1 and phosphatidylinositol 3 -kinase.Receptors that have an intrinsic tyrosine kinase domain recruit and activate a variety of signal transducers. Insulin receptor substrate 1 (IRS-1) 1 is a cytosolic protein of ϳ180 kDa in mass that is tyrosyl-phosphorylated at multiple sites through activated insulin and insulin-like growth factor 1 (IGF-1) receptors (1, 2). An L(X) 4 NPXY(p)XSXP motif has been identified in the insulin receptor as being important for the recruitment of the IRS proteins. IRS-1 contains multiple YMXM and YXXM tyrosine motifs, which when phosphorylated can recruit Src homology 2 domain-containing proteins, including the p85␣ regulatory subunit of PI 3Ј-kinase, SHP-2, Grb-2, Crk, and Nck (3, 4). Phosphorylated IRS-1, therefore, can mediate a variety of responses including a mitogenic response and activation of PI 3Ј-kinase.Common themes involving the role of tyrosine kinases and proteins with Src homology 2 domains have emerged to describe broadly the mechanism of signal transduction by many growth factors and cytokines. Signal transduction pathways utilizing the JAK (Janus kinase) family of protein-tyrosine kinases and the STATs (signal transducers and activators of transcription) are activated in response to polypeptide ligands including many cytokines, some growth factors and the interferons (IFNs). STAT activation mediated through the JAKs occurs in receptor complexes at the cell membrane. There are four known mammalian JAKs: JAK1, JAK2, JAK3, and T...