Essential Role of Signal Transducer and Activator of Transcription (Stat)5a but Not Stat5b for Flt3-Dependent Signaling

Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 10/2000; 192(5):719-28.
Source: PubMed


The receptor tyrosine kinase Flt3 plays an important role in proliferation and survival of hematopoietic stem and progenitor cells. Although some post-receptor signaling events of Flt3 have been characterized, the involvement of the Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway in Flt3 signaling has not been thoroughly evaluated. To this aim, we examined whether Flt3 activates the Jak/Stat pathway in Baf3/Flt3 cells, a line stably expressing human Flt3 receptor. Stat5a, but not Stats 1-4, 5b, or 6, was potently activated by Flt3 ligand (FL) stimulation. Interestingly, FL did not activate any Jaks. Activation of Stat5a required the kinase activity of Flt3. A selective role for Stat5a in the proliferative response of primary hematopoietic progenitor cells to FL was documented, as FL did not act on progenitors from marrows of Stat5a(-/-) mice, but did stimulate/costimulate proliferation of these cells from Stat5a(+/+), Stat5b(-/-), and Stat5b(+/+) mice. Thus, Stat5a is essential for at least certain effects of FL. Moreover, our data confirm that Stat5a and Stat5b are not redundant, but rather are at least partially distinctive in their function.

Download full-text


Available from: Seiji Fukuda, Oct 10, 2014
  • Source
    • "As seen in Figure 5F, BM cells derived from leukemic mice bearing the KITD814V mutation that were treated with F-14 also showed a reduction in Stat5 activation and nuclear accumulation of Rac1, as compared to cells derived from vehicle (DMSO)-treated mice (Figure 5F, lane 1 versus 2). Active Stat5 downstream of FLT3ITD translocates to the nucleus to bind DNA and express Stat5-responsive genes like c-Myc and BclXL that play a crucial role in leukemogenesis (Li et al., 2007; Zhang et al., 2000). We next performed quantitative RT-PCR (qRT-PCR) analysis to determine the relative expression of c-Myc and BclXL genes in FLT3ITD cells treated with F-14. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK) whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Nov 2014 · Cell Reports
  • Source
    • "STATs are transcription factors that may play oncogenic roles in the development of SCCHN [14], where Stat proteins may be activated by EGFR and/or SRC [15] or by non- EGFR pathways [16]. STATs act through receptor tyrosine kinases or cytokines [14], whereas their effects on gene transcription and cell function are described as distinct and nonredundant [17] [18]. SRC family kinases (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog, SFKs) and STATs have been associated with resistance to pharmaceutical EGFR targeting in SCCHN. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The anti-epidermal growth factor receptor antibody cetuximab (Erbitux, CTX) is currently used for the treatment of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), as yet with modest effectiveness, prompting for the identification of response predictors to this treatment and for the targeting of additional pathways implicated in this disease. Within this scope, we investigated the effect of SRC/STAT pathway components on LA-SCCHN patient outcome. SRC, STAT1, STAT3, STAT5A, STAT5B, ANXA1, CAV1, IGFBP2, EPHA2, EPHB2, and MSN relative gene expression, as well as Stat protein activation, were assessed on LA-SCCHN tumor tissues from 35 patients treated with combined radiotherapy (RT) and CTX-based regimens. Stat1, Stat3, and Stat5 proteins were usually found activated in neoplastic nuclei (70.4%, 85.7%, and 70.8%, respectively). Activated Stat3 and Stat5 were associated with each other (P = .017) and with a CAV1(high)/MSN(high)/IGFBP2(low) profile. All patients with tumors expressing high STAT5A/EPHA2 experienced a complete response on RT-CTX-based treatments (12/15 complete responders, P < .0001) and a longer progression-free survival (P = .024). Few tumors expressed high ANXA1/CAV1/EPHA2 and low IGFBP2, a putative dasatinib response-related profile, whereas high ANXA1 was associated with shorter overall survival (P = .003). In conclusion, Stat activation is common in LA-SCCHN, where overexpression of STAT5A and EPHA2 may predict for response to RT-CTX treatments. The STAT5A/EPHA2 profile seems of particular interest for validation in larger cohorts and in multiple tumor types because markers for the positive selection of patients to benefit from CTX-containing treatments are currently lacking.
    Full-text · Article · Feb 2011 · Translational oncology
  • Source
    • "r HSC ( Kawada and Ogawa , 2001 ; McKinney - Freeman et al . , 2002 ) , but the role of such local HSC in vaccine - induced immunity is unclear . If these cells expressed Flt - 3 , it is tempting to speculate that engagement of this receptor by Flt - 3 L could induce signaling cascades resulting in activation of genes involved in innate immunity ( Zhang et al . , 2000 ) . It is an intriguing possibility , given the role of FLex and / or GM - CSF in inducing an expansion and mobilization of DCs to the sites ( i . m . or i . d . ) of plasmid injection ( Mwangi et al . , 2002 ; Peretz et al . , 2002 ; Sang et al . , 2003 ; Westermann et al . , 2004 ) . Production of gp120 - specific antibodies indicate "
    [Show abstract] [Hide abstract]
    ABSTRACT: In this study, we have taken advantage of the unique property of a potent dendritic cell (DC) growth factor, Flt-3 ligand (FL), which could act as a vaccine adjuvant. Accordingly, a single injection of plasmid DNA coding for soluble FL (FLex) was shown to induce large numbers of DCs in various tissue compartments and was critical for generating high frequencies of antigen-specific (HIV gp120 and LCMV NP) immune responses in mice. Interestingly, this enhanced level of immune response is strictly dependent on the co-delivery (i.m.) of the DNA vaccines and hFLex DNA to mice harboring large numbers of DCs. The high frequencies of antigen-specific CD8(+) T cells were largely associated with the expansion phase of DCs in vivo. However, DC expansion and immune enhancement have not reciprocally maintained a linear correlation, suggesting that other factors, cytokines/chemokines, which have the potential to modulate the microenvironment of DCs, could influence immunological outcome in this vaccination modality.
    Full-text · Article · Jun 2006 · Virology
Show more