Neoplasia Driven by Mutant c-<i>KIT</i> Is Mediated by Intracellular, Not Plasma Membrane, Receptor Signaling

Zhang, Xiang; Kreisel, Frederike; Cain, Jennifer; Colson, AnnaLynn; Tomasson, Michael H.

doi:10.1128/mcb.01153-06

Cited by 108 publications

(135 citation statements)

References 40 publications

Supporting

Mentioning

121

Contrasting

Order By: Relevance

“…20 Similar intracellular retention and corroborating STAT5 activation was also observed for oncogenic KIT mutants. 47 Here, we show the same localization-dependent skewed signaling behavior for F/PDGFRa. Together, all these data show that increased intracellular localization shifts the signaling capacities of the PDGFR/KIT/ Flt3 family of receptors in a variety of cell types.…”

Section: Discussionsupporting

confidence: 55%

The oncogenic FIP1L1-PDGFRαfusion protein displays skewed signaling properties compared to its wild-type PDGFRαcounterpart

et al. 2015

View full text Add to dashboard Cite

ABSTRACT. Aberrant activation of oncogenic kinases is frequently observed in human cancers, but the underlying mechanism and resulting effects on global signaling are incompletely understood. Here, we demonstrate that the oncogenic FIP1L1-PDGFRa kinase exhibits a significantly different signaling pattern compared to its PDGFRa wild type counterpart. Interestingly, the activation of primarily membrane-based signal transduction processes (such as PI3-kinase-and MAP-kinase-pathways) is remarkably shifted toward a prominent activation of STAT factors. This diverging signaling pattern compared to classical PDGF-receptor signaling is partially coupled to the aberrant cytoplasmic localization of the oncogene, since membrane targeting of FIP1L1-PDGFRa restores activation of MAPK-and PI3K-pathways. In stark contrast to the classical cytokine-induced STAT activation process, STAT activation by FIP1L1-PDGFRa does neither require Janus kinase activity nor Src kinase activity. Furthermore, we investigated the mechanism of STAT5 activation via FIP1L1-PDGFRa in more detail and found that STAT5 activation does not involve an SH2-domain-mediated binding mechanism. We thus demonstrate that STAT5 activation occurs via a non-canonical activation mechanism in which STAT5 may be subject to a direct phosphorylation by FIP1L1-PDGFRa.

show abstract

Section: Discussionsupporting

confidence: 55%

The oncogenic FIP1L1-PDGFRαfusion protein displays skewed signaling properties compared to its wild-type PDGFRαcounterpart

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Although cell surface expression of the KIT D816V receptor is reduced and its localization shifted to the Golgi apparatus, it has been demonstrated that KIT D816V activates the major signaling pathways that are also induced by the ligand-dependent wild-type receptor. 25 Implication of the D816V mutation in the pathogenesis of myeloproliferative disease demonstrates a critical role of KIT D816V transduced signals in the development of myeloid cells. 26,27 Although extrapolations regarding the physiological mechanisms of Kit signaling during myeloid cell differentiation must be made with caution, it is thus reasonable that similar signaling events are activated by the mutant KIT D816V receptor and valuable insights can be provided by such a model.…”

Section: Resultsmentioning

confidence: 99%

“…The receptor consists of the murine extracellular and transmembrane domains and the human intracellular domain (Supplementary Figure 1A) and shows fully transforming potential in murine cells. 25 We linked the KIT cDNA to a green fluorescent protein (GFP) coding sequence from copepod Pontellina plumata by a viral 2A-sequence 28 to generate the GFP-2A-KIT D818V fusion protein, hereafter called KIT D816V . During translation the 2A-peptide mediates separation of GFP and KIT, allowing reliable tracking with minimal alteration of the receptor.…”

Section: Resultsmentioning

confidence: 99%

Kit transduced signals counteract erythroid maturation by MAPK-dependent modulation of erythropoietin signaling and apoptosis induction in mouse fetal liver

et al. 2014

View full text Add to dashboard Cite

Signaling by the stem cell factor receptor Kit in hematopoietic stem and progenitor cells is functionally associated with the regulation of cellular proliferation, differentiation and survival. Expression of the receptor is downregulated upon terminal differentiation in most lineages, including red blood cell terminal maturation, suggesting that omission of Kit transduced signals is a prerequisite for the differentiation process to occur. However, the molecular mechanisms by which Kit signaling preserves the undifferentiated state of progenitor cells are not yet characterized in detail. In this study, we generated a mouse model for inducible expression of a Kit receptor carrying an activating mutation and studied its effects on fetal liver hematopoiesis. We found that sustained Kit signaling leads to expansion of erythroid precursors and interferes with terminal maturation beyond the erythroblast stage. Primary KIT D816V erythroblasts stimulated to differentiate fail to exit cell cycle and show elevated rates of apoptosis because of insufficient induction of survival factors. They further retain expression of progenitor cell associated factors c-Myc, c-Myb and GATA-2 and inefficiently upregulate erythroid transcription factors GATA-1, Klf1 and Tal1. In KIT D816V erythroblasts we found constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, elevated expression of the src kinase family member Lyn and impaired Akt activation in response to erythropoietin. We demonstrate that the block in differentiation is partially rescued by MAPK inhibition, and completely rescued by the multikinase inhibitor Dasatinib. These results show that a crosstalk between Kit and erythropoietin receptor signaling cascades exists and that continuous Kit signaling, partly mediated by the MAPK pathway, interferes with this crosstalk. Erythroid cell proliferation, differentiation and survival are tightly regulated to ensure supply of the organism with sufficient numbers of red blood cells. Regulation of these processes is governed by two major signaling receptors, the stem cell factor (SCF) receptor Kit and the erythropoietin receptor (EpoR). Kit is expressed in hematopoietic stem and progenitor cells and becomes downregulated upon differentiation of colony-forming unit erythroid cells.1 EpoR gets upregulated after erythroid commitment and is expressed until later erythroblast stages. Both receptors are essential for erythroid development, as Kit or EpoR-deficient mice die in utero because of impaired fetal liver erythropoiesis.3,4 The roles of Kit and EpoR in erythropoiesis are partially overlapping and signal integration after co-stimulation results in proliferative synergy and enhanced survival. [5][6][7] However, Kit has been attributed a primary role in proliferation, 8,9 whereas EpoR has its main role in mediating differentiation and survival.

show abstract

“…For immunostaining, cells were directly fixed in 2% paraformaldehyde, permeabilized with ethanol, and stained with primary antibodies for 12 hours followed by labeled secondary antibodies. 40,41 The primary antibodies used were as follows: anti-Fms rat IgG (clone 3-4A4-E4; Abcam, Cambridge, MA), anti-GM130 mouse IgG (Transduction Laboratories), anti-CD8 rabbit IgG (H-160; Santa Cruz Biotechnology), and rabbit IgG specific for Hck phosphorylated at Tyr411 (Santa Cruz Biotechnology). The labeled secondary antibodies used were as follows: anti-rat IgG-AlexaFluo488, anti-mouse IgG-AlexaFluo568, and anti-rabbit IgG-AlexaFluo488 (Molecular Probes, Eugene, OR).…”

mentioning

confidence: 99%

Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor

Hiyoshi¹,

Suzu²,

Yoshidomi³

et al. 2008

Blood

View full text Add to dashboard Cite

Nef is a multifunctional pathogenetic protein of HIV-1, the interaction of which with Hck, a Src tyrosine kinase highly expressed in macrophages, has been shown to be responsible for the development of AIDS. However, how the Nef-Hck interaction leads to the functional aberration of macrophages is poorly understood. We recently showed that Nef markedly inhibited the activity of macrophage colonystimulating factor (M-CSF), a primary cytokine for macrophages. Here IntroductionHIV-1 infections lead to the development of AIDS by causing progressive degeneration of the immune system. [1][2][3] The main cellular targets of HIV-1 are CD4 ϩ T cells and macrophages, and the depletion of CD4 ϩ T cells caused by an infection is suggested to account for many aspects of the pathogenesis of HIV-1. [1][2][3] Meanwhile, a number of studies have revealed the functional aberration of HIV-1-infected macrophages. 4,5 Infected macrophages showed an altered profile of the production of cytokine/chemokines 4 or migratory capacity, 5 which might contribute to the uncontrolled homeostasis of the immune system. Indeed, functional analyses of HIV-1 Nef protein have revealed that macrophages as well as CD4 ϩ T cells play an important role in the development of AIDS.Nef is a 25-to 30-kDa protein with no enzymatic activity encoded by the HIV-1 genome. 6,7 Studies of HIV-1-infected patients have clearly demonstrated Nef to be a critical determinant of the development of AIDS: HIV-1 strains without an intact Nef gene were frequently isolated from nonprogressive long-term survivors. 8,9 Subsequent study of HIV-1 transgenic mice confirmed the pathogenetic activity of Nef: targeted expression of the entire coding sequence of HIV-1 in CD4 ϩ T cells and macrophages caused a severe AIDS-like disease in mice, which was completely abolished by the disruption of the Nef gene. 10 Importantly, only an amino acid substitution in the proline-rich (PxxP) motifs of Nef was sufficient to protect mice from the development of AIDS-like disease. 11 A number of studies have revealed that Nef interacts with a subset of cellular Src family tyrosine kinases, via the PxxP motifs. 12-15 The Nef PxxP motifs had an affinity for the Src homology (SH3) domain of Hck, Lyn, and possibly c-Src, but not of Fgr, Fyn, Lck, In particular, the interaction between the Nef PxxP motifs and the Hck SH3 domain was likely to be important, because the interaction caused the activation of Hck. [13][14][15] Indeed, a study with HIV-1 transgenic mice clearly demonstrated the importance of the Nef-Hck interaction for the development of AIDS: the appearance of the AIDS-like disease was significantly delayed when the HIV-1 transgenic mice expressing an intact Nef gene were crossed with an hck Ϫ/Ϫ background. 11 Given that Hck is expressed in macrophages but not in CD4 ϩ T cells, 16 the finding indicates that the Nef-Hck interaction in macrophages is at least in part responsible for the development of AIDS. However, little is known of the molecular mechanisms by which the Nef-Hck interaction c...

show abstract

Neoplasia Driven by Mutant c-KIT Is Mediated by Intracellular, Not Plasma Membrane, Receptor Signaling

Cited by 108 publications

References 40 publications

The oncogenic FIP1L1-PDGFRαfusion protein displays skewed signaling properties compared to its wild-type PDGFRαcounterpart

The oncogenic FIP1L1-PDGFRαfusion protein displays skewed signaling properties compared to its wild-type PDGFRαcounterpart

Kit transduced signals counteract erythroid maturation by MAPK-dependent modulation of erythropoietin signaling and apoptosis induction in mouse fetal liver

Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor

Contact Info

Product

Resources

About