The interaction between KDR and interleukin-3 receptor (IL-3R) beta common modulates tumor neovascularization

Dentelli, Patrizia; Rosso, Arturo; Garbarino, Giovanni; Calvi, Cristina; Lombard, Emanuela; Stefano, Paola Di; Defilippi, Paola; Pegoraro, Luigi; Brizzi, Maria Felice

doi:10.1038/sj.onc.1208786

Cited by 13 publications

(11 citation statements)

References 49 publications

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“…Dentelli et al . have demonstrated that a ∆455 βc mutant, where the entire βc intracellular domain is lacking, conferred a reduced response to both IL‐3 and VEGF for mouse endothelial cell (H‐END and HMEC‐1 cells) migration, invasion, tumor vascular density, and metastasis, which was mediated by STAT5A and Rac1. Thus, the IL‐3 and VEGF receptors appear to functionally heterodimerize leading to a convergence of signaling.…”

Section: Interaction With Other Cytokine Receptors At the Cell Surfacementioning

confidence: 99%

“…Activation of these receptors then initiated their migration to lipid rafts and sustained p38 mitogen-activated protein kinase activation, which was required for the proliferation and survival of primary AML blasts (238). Dentelli et al (239) have demonstrated that a Δ455 bc mutant, where the entire bc intracellular domain is lacking, conferred a reduced response to both IL-3 and VEGF for mouse endothelial cell (H-END and HMEC-1 cells) migration, invasion, tumor vascular density, and metastasis, which was mediated by STAT5A and Rac1. Thus, the IL-3 and VEGF receptors appear to functionally heterodimerize leading to a convergence of signaling.…”

Section: Interactions Between Epo Vegf and Il-3/gm-csf/il-5 Receptorsmentioning

confidence: 99%

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The GM–CSF/IL‐3/IL‐5 cytokine receptor family: from ligand recognition to initiation of signaling

Broughton

Dhagat

Hercus

et al. 2012

Immunological Reviews

203

162

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Granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 are members of a discrete family of cytokines that regulates the growth, differentiation, migration and effector function activities of many hematopoietic cells and immunocytes. These cytokines are involved in normal responses to infectious agents, bridging innate and adaptive immunity. However, in certain cases, the overexpression of these cytokines or their receptors can lead to excessive or aberrant initiation of signaling resulting in pathological conditions, with chronic inflammatory diseases and myeloid leukemias the most notable examples. Recent crystal structures of the GM-CSF receptor ternary complex and the IL-5 binary complex have revealed new paradigms of cytokine receptor activation. Together with a wealth of associated structure-function studies, they have significantly enhanced our understanding of how these receptors recognize cytokines and initiate signals across cell membranes. Importantly, these structures provide opportunities for structure-based approaches for the discovery of novel and disease-specific therapeutics. In addition, recent biochemical evidence has suggested that the GM-CSF/IL-3/IL-5 receptor family is capable of interacting productively with other membrane proteins at the cell surface. Such interactions may afford additional or unique biological activities and might be harnessed for selective modulation of the function of these receptors in disease.

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Section: Interaction With Other Cytokine Receptors At the Cell Surfacementioning

confidence: 99%

Section: Interactions Between Epo Vegf and Il-3/gm-csf/il-5 Receptorsmentioning

confidence: 99%

The GM–CSF/IL‐3/IL‐5 cytokine receptor family: from ligand recognition to initiation of signaling

Broughton

Dhagat

Hercus

et al. 2012

Immunological Reviews

203

162

View full text Add to dashboard Cite

show abstract

“…DNA was stained with propidium Assay for Rac1-GTP Loading-MC transfected with the dominant negative mutant of Rac-1 (V12N17Rac) or the corresponding empty vector (pEXV) were serum-deprived for 24 h and untreated or treated with ox-LDL. Cells were lysed as described (31). Lysates were clarified by centrifugation and incubated with recombinant GST-PAK precoupled to Sepharose-glutathione beads (Amersham Biosciences) and then washed three times in lysis buffer (32).…”

Section: Methodsmentioning

confidence: 99%

Oxidative Stress-mediated Mesangial Cell Proliferation Requires RAC-1/Reactive Oxygen Species Production and β4 Integrin Expression

Dentelli

Rosso

Zeoli

et al. 2007

Journal of Biological Chemistry

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Lipid abnormalities and oxidative stress, by stimulating mesangial cell (MC) proliferation, can contribute to the development of diabetes-associated renal disease. In this study we investigated the molecular events elicited by oxidized low density lipoproteins (ox-LDL) in MC. We demonstrate that in MC cultured in the presence of ox-LDL, survival and mitogenic signals on Akt and Erk1/2 MAPK pathways are induced, respectively. Moreover, as shown by the expression of the dominant negative Rac-1 construct, we first report that ox-LDL-mediated cell survival and cell cycle progression depend on Rac-1 GTPase-mediated reactive oxygen species production and on epidermal growth factor receptor transactivation. By silencing Akt and blocking Erk1/2 MAPK pathways, we also demonstrate that these signals are downstream to Rac-1/reactive oxygen species production and epidermal growth factor receptor activation. Finally, by endogenous depletion of ␤4 integrin, expressed in MC, we provide evidence that the expression of this adhesion molecule is essential for ox-LDL-mediated MC dysfunction. Our data identify a novel signaling pathway involved in oxidative stress-induced diabetes-associated renal disease and provide the rationale for therapeutically targeting ␤4 integrin.Abnormalities in lipoprotein metabolism are commonly observed in patients with renal disease. Specifically, hyperlipidemia and glomerular lipid deposition of atherogenic lipoproteins (low density lipoproteins (LDL), 2 and their oxidized variants, ox-LDL) are implicated in key pathobiological processes involved in the development of glomerular diseases, including mesangial cell (MC) hypercellularity (1). The relevance of mitogen intracellular signaling in mesangial proliferative disease has only recently been recognized (2). Indeed, accumulation of atherogenic lipoproteins within the glomerulus, by activating membrane receptor protein-tyrosine kinases (RPTK), such as the epidermal growth factor receptor (EGFR), triggers MAPK cascades leading to cyclin/cyclin-dependent kinase activation of DNA synthesis and MC proliferation (2). Moreover, in smooth muscle cells, ox-LDL (3) has been shown to trigger the phosphatidylinositol 3-kinase/Akt signaling pathway (4). These data thus suggest that atherogenic lipoproteins may act as one of the major endogenous modulators for mitogenic signaling response within the glomerulus.Although superoxide anions and hydrogen peroxide are generally considered to be toxic, recent evidence suggests that the production of the reactive oxygen species (ROS) might be an integral component of membrane receptor signaling (5). In mammalian cells, a vast array of intracellular stimuli have been shown to induce a transient increase in the intracellular ROS concentrations, and specific inhibition of ROS generation results in a complete blockage of stimulant-dependent signaling (5). In particular, growth factor-mediated ROS generation seems to be necessary for propagation of downstream mitogenic and antiapoptotic signals (5).Rho family GTPases are imp...

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“…Interestingly, previous studies have shown that endothelial cells highly expressed the common β chain of GM‐CSF and IL‐3 receptors and respond to IL‐3 and GM‐CSF with induction of proliferation and migration (Colotta et al , 1993). Furthermore, studies carried out in HEK 293 cells, a transformed endothelial cell line expressing both KDR and the IL‐3R beta chain, showed that both IL‐3 and GM‐CSF stimulation lead to the formation of a KDR/IL‐3R beta c complex (Dentelli et al , 2005).…”

Section: Discussionmentioning

confidence: 99%

Colocalization of the VEGF‐R2 and the common IL‐3/GM‐CSF receptor beta chain to lipid rafts leads to enhanced p38 activation

et al. 2009

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Summary Previous studies suggested an important role for vascular endothelial growth factor (VEGF) and its receptors in postnatal haemopoiesis. However, it is unclear how VEGF receptor (VEGFR) signalling could interact with that issued from the activation of haematopoietic growth factor receptors. To elucidate this point we explored VEGF‐R2 and granulocyte‐macrophage colony‐stimulating factor receptor (GM‐CSFR) membrane localization and cell signalling in TF1‐KDR cells (TF1 leukaemic cells that overexpress VEGF‐R2/KDR). Activation of either GM‐CSFR or VEGF‐R2 was shown to determine the migration of both receptor elements (VEGF‐R2 and the common β‐chain of the GM‐CSFR) to lipid rafts. The study of receptor phosphorylation showed that GM‐CSF induced the phosphorylation of its own receptor and the transphosphorylation of VEGF‐R2; on the other hand, VEGF triggered the phosphorylation of its receptor and transphosphorylated the β‐chain of the GM‐CSFR. Co‐stimulation of TF1‐KDR cells with both GM‐CSF and VEGF‐A resulted in massive migration of both the common GM‐CSFR β‐chain and VEGF‐R2 to lipid rafts and sustained p38 mitogen‐activated protein kinase activation. Disruption of lipid rafts inhibited the capacity of both GM‐CSF and VEGF‐A to activate p38. Experiments with specific p38 inhibitors showed that p38 activation was required to sustain the VEGF‐ and GM‐CSF‐dependent proliferation of TF1‐KDR and the survival of primary acute myeloid leukaemia blasts.

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The interaction between KDR and interleukin-3 receptor (IL-3R) beta common modulates tumor neovascularization

Cited by 13 publications

References 49 publications

The GM–CSF/IL‐3/IL‐5 cytokine receptor family: from ligand recognition to initiation of signaling

The GM–CSF/IL‐3/IL‐5 cytokine receptor family: from ligand recognition to initiation of signaling

Oxidative Stress-mediated Mesangial Cell Proliferation Requires RAC-1/Reactive Oxygen Species Production and β4 Integrin Expression

Colocalization of the VEGF‐R2 and the common IL‐3/GM‐CSF receptor beta chain to lipid rafts leads to enhanced p38 activation

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