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Mitogenic Synergy Through Multilevel Convergence of Hepatocyte Growth Factor and Interleukin-4 Signaling Pathways

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Mitogenic Synergy Through Multilevel Convergence of Hepatocyte Growth Factor and Interleukin-4 Signaling Pathways Oncogene (2002) 21, 2201 ± 2211 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc Mitogenic synergy through multilevel convergence of hepatocyte growth factor and interleukin-4 signaling pathways Regina M Day1,2,3, Lilian Soon1,2,3, Diane Breckenridge1,2,3, Benjamin Bridges1,2,3, Bharvin KR Patel1,2,3, Ling Mei Wang1,2,3, Seth J Corey1,2 and Donald P Bottaro*,1,2,3 1Laboratory of Cellular and Molecular Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; 2Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; 3Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Hepatocyte growth factor (HGF) regulates various Introduction physiological and developmental processes in concert with other growth factors, cytokines and hormones. We Hepatocyte growth factor (HGF) stimulates mitogen- examined interactions between cell signaling events esis, motogenesis, and morphogenesis in a wide range elicited by HGF and the cytokine interleukin (IL)-4, in of cellular targets including epithelial and endothelial the IL-3-dependent murine myeloid cell line 32D cells, hematopoietic cells, neurons, melanocytes, as well transfected with the human HGF receptor, c-Met. as hepatocytes (reviewed in Michalopoulos and De- HGF was a potent mitogen in these cells, and prevented Frances, 1997; Rubin et al., 1993; Zarnegar and apoptosis in response to IL-3 withdrawal. IL-4 showed Michalopoulos, 1995). These pleiotropic eects play modest anti-apoptotic activity, but no signi®cant mito- important roles during development, organogenesis genic activity. IL-4 synergistically enhanced HGF- and tissue regeneration. HGF is essential for the stimulated DNA synthesis, whereas only additive pre- normal development of both liver and placenta vention of apoptosis was observed. IL-4 did not enhance (reviewed in Birchmeier and Gherardi, 1998), con- HGF-dependent tyrosine phosphorylation of c-Met or tributes to neural development (reviewed in Streit and Shc. In contrast, HGF-stimulated activation of MAP Stern, 1997), branching morphogenesis in various kinases was enhanced by IL-4, suggesting that the IL-4 organs (reviewed in Birchmeier et al., 1997), and and HGF signaling pathways converge upstream of these promotes kidney and lung regeneration (Yanagita et events. Although phosphatidylinositol 3-kinase (PI3K) al., 1993; Balkovetz and Lipschutz, 1999). inhibitors diminished HGF-induced mitogenesis, anti- Among hematopoietic tissues, HGF is produced by apoptosis, and MAP kinase activation, IL-4 enhanced bone marrow stromal cells (Weimar et al., 1998), and c- HGF signaling persisted even in the presence of these Met is expressed in CD34+ hematopoietic progenitor inhibitors. IL-4 enhancement of HGF signaling was cells (HPC) derived from bone marrow, peripheral partially blocked in 32D/c-Met cells treated with blood, and cord blood (Weimar et al., 1998; Kmiecik et inhibitors of MEK1 or c-Src kinases, completely blocked al., 1992; Ikehara, 1996). HGF promotes the prolifera- by expression of a catalytically inactive mutant of Janus tion, adhesion, and survival of CD34+ HPC (Weimar et kinase 3 (Jak3), and increased in 32D/c-Met cells al., 1998; Kmiecik et al., 1992), and acts synergistically overexpressing STAT6. Our results suggest that the with interleukin (IL)-3 or granulocyte-macrophage IL-4 and HGF pathways converge at multiple levels, and colony stimulating factor (GM-CSF) to increase colony that IL-4-dependent Jak3 and STAT6 activities mod- forming units in culture by CD34+ HPC in vitro ulate signaling events independent of PI3K to enhance (Kmiecik et al., 1992; Ikehara, 1996). Erythropoietin HGF-dependent mitogenesis in myeloid cells, and (EPO) and HGF also act synergistically to induce the possibly other common cellular targets. formation of erythroid burst-forming unit colonies from Oncogene (2002) 21, 2201 ± 2211. DOI: 10.1038/sj/ CD34+ HPC (Ikehara, 1996; Iguchi et al., 1999). HGF onc/1205289 compensates for de®ciencies in stem cell proliferation observed in mice harboring dominant mutations in the Keywords: growth factor; cytokine; signal transduc- genes encoding stem cell factor (SCF) or its receptor, c- tion; cell proliferation kit (Yu et al., 1998). HGF enhances antibody production in mature B cells (Delaney et al., 1993), and stimulates rapid cytoskeletal changes, adhesion, and migration in peripheral blood T cells (Adams et al., 1994). In addition to roles in normal development and adult *Correspondence: DP Bottaro, Department of Cell and Molecular homeostasis, HGF signaling is strongly linked to cancer, Biology, EntreMed, Inc., Rockville, Maryland, MD 20850 USA; including colon, breast, lung, thyroid and renal E-mail: [email protected] Received 2 May 2000; revised 3 January 2002; accepted 7 January carcinomas, melanoma and several sarcomas, as well as 2002 glioblastoma (reviewed in Vande Woude et al., 1997). HGF and IL-4 mitogenic synergy RM Day et al 2202 Among hematopoietic tumors, many human leukemia Results cell lines secrete HGF in vivo and in vitro, including those derived from adult T-cell leukemia, acute lymphoblastic Mitogenic synergy between HGF and IL-4 leukemia, multiple myeloma (MM), acute undieren- tiated leukemia, chronic myelocytic leukemia, acute The mitogenic response of 32D/c-Met cells to HGF is myeloblastic leukemia, and acute promyelocytic leuke- shown in Figure 1a. Increased DNA synthesis was mia (Gohda et al., 1995). HGF promotes the adhesion of detectable at 50 ng/ml (0.55 nM) HGF, and reached B-lymphoma cells to the extracellular matrix (Weimar et maximal levels at 1 mg/ml (11 nM;ED50=3.3 nM). al., 1997), and the overproduction of HGF associated 32D/c-Met cells also express low levels of IL-4 with MM has been linked to the extensive bone marrow receptor, but IL-4 is not mitogenic in these cells (Wang angiogenesis and bone destruction characteristic of that et al., 1993). As shown in Figure 1b, IL-4 at disease (Borset et al., 1999). concentrations of up to 100 ng/ml did not stimulate An emerging theme in our understanding of HGF signi®cant [3H]-thymidine incorporation. However, IL- action is the modulation of its biological activities by 4 signi®cantly enhanced HGF-stimulated [3H]-thymi- other cytokines. Among the many cytokines whose dine incorporation in a dose-dependent manner (Figure actions coincide spatially and temporally with those of 1b). These results show that the eects of HGF with HGF, few are as ubiquitous as Interleukin (IL)-4. IL-4 IL-4 far exceeded the sum of either mitogen adminis- is produced predominantly by T cells, mast cells and tered alone, indicating mitogenic synergy between IL-4 basophils (Paul, 1991). The IL-4 receptor, IL4Ra,a and HGF in 32D/c-Met cells. We estimate that IL-4 member of the hematopoietin/cytokine receptor super- (1 ng/ml) increased the ED50 of HGF approximately family, is expressed on both hematopoietic and non- 3 ± 5-fold. Similar eects have been observed in hematopoietic cells (Cosman, 1993). IL-4 stimulates the epithelial cells, such as Balb/MK keratinocytes (JS proliferation and dierentiation of B cells, the Rubin and WG Taylor, personal communication). proliferation of T cells and mast cells, and regulates Heparan sulfate proteoglycan (HSPG) has been the lymphokine producing phenotype of CD4+ T shown to modulate HGF signaling in several target cell lymphocytes (Keegan et al., 1994). In non-hematopoie- types, including Baf3 and 32D, which lack abundant cell tic cells such as ®broblasts and epithelial cells, IL-4 surface HSPG (Day et al., 1999; Schwall et al., 1996; modulates extracellular matrix production, causes Sakata et al., 1997). Soluble heparin (10 mg/ml), which changes in morphology and cytoskeletal organization, may substitute for cell-surface HSPG to some extent, and stimulates chemotaxis (Postlethwaite and Seyer, enhanced HGF mitogenic activity in 32D/c-Met cells at 1991; Postlethwaite et al., 1992). IL-4 can also least threefold, but did not impart mitogenic activity to stimulate the dierentiation of human carcinoma cells, the truncated HGF isoform, HGF/NK2 (Figure 2). The and thereby block their proliferation (Hoon et al., eects of heparin were most striking at low levels of 1991; Morisaki et al., 1992, 1994). The biological HGF (2 and 20 ng/ml), and decreased at very high eects of IL-4 are also in¯uenced by other cytokines (200 ng/ml) HGF concentrations, as maximal mitogenic and growth factors. IL-4 complements IL-2 in T-cell stimulation was reached (Figure 2a). The simultaneous tumor lines for ex vivo autocrine growth and for in vivo addition of both soluble heparin and IL-4 to 32D/c-Met tumorigenicity (Hassuneh et al., 1997), acts synergisti- cells increased the mitogenic activity of HGF to a greater cally with platelet-derived growth factor (PDGF) in extent than either factor alone. As shown in Figure 2a, mitogenesis (Patel et al., 1996), and inhibits HGF- IL-4 (1 ng/ml) or heparin (10 mg/ml) alone enhanced stimulated migration of colon carcinoma cells (Uchiya- mitogenic activity of HGF (2 ng/ml) about fourfold. In ma et al., 1996). the presence of both IL-4 and heparin, HGF-dependent We investigated the eects of IL-4 on HGF mitogenic activity was more than 20-fold higher than biological activities in the myeloid cell line 32D that of HGF alone (Figure 2a). In addition to dierences transfected with human HGF receptor (32D/c-Met in their presumed sites of action, the ability of soluble cells; Day et al., 1999). HGF stimulated mitogenesis heparin to further enhance the HGF/IL-4 mitogenic and prevented apoptosis in response to IL-3 with- synergy supports the hypothesis that IL-4 and heparin drawal. IL-4, in contrast, showed modest anti- facilitate HGF mitogenicity by distinct mechanisms: apoptotic activity and no mitogenic activity. However, heparin at the level of HGF-c-Met interaction, and IL-4 IL-4 synergistically enhanced HGF-stimulated DNA at the level of intracellular signaling.
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