PKCδ plays opposite roles in growth mediated by wild-type Kit and an oncogenic Kit mutant

Jelacic, Tanya; Linnekin, Diana

doi:10.1182/blood-2004-04-1450

Cited by 15 publications

(15 citation statements)

References 62 publications

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“…This is in contrast to another report [24] that suggested a differentiating but not transforming potential for the mutation, which nevertheless probably participates in enhancing mast cell chemotaxis [25] and clustering [26]. Mutant Kit signaling might involve both PI3K [27] and Src [28] participation although utilization of pathway molecules might be different between the wild-type and mutant protein [29]. …”

Section: Mastocytosis-relevant Kit Mutationscontrasting

confidence: 51%

<i>KIT</i> and Mastocytosis

Lim¹,

Pardanani²,

Tefferi³

2008

Acta Haematol

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KIT is a receptor tyrosine kinase that is functionally relevant for hematopoiesis, mast cell development and function, gametogenesis and melanogenesis. Normal KIT signaling requires binding to stem cell factor, and PI3K-Akt is one of the putative effector pathways. In humans, germline loss-of-function KIT mutations have been associated with piebaldism – an autosomal dominant condition characterized by depigmented patches of skin and hair. Gain-of-function KIT mutations are usually acquired and have been associated with myeloid malignancies including core binding factor acute myeloid leukemia and systemic mastocytosis (SM), germ cell tumors, gastrointestinal stromal tumors and sinonasal T cell lymphomas. KITD816V is the most prevalent KIT mutation in mast cell disease and occurs in more than 90% of the cases that fulfill the World Health Organization diagnostic criteria for SM. However, its precise pathogenetic contribution is not well understood. In clinical practice, SM is considered either indolent or aggressive depending on the respective absence or presence of symptomatic target organ dysfunction aside from skin disease. In general, conventional therapy for SM is suboptimal, and efforts are under way to develop and employ small molecule drugs that target mutant KIT.

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Section: Mastocytosis-relevant Kit Mutationscontrasting

confidence: 51%

<i>KIT</i> and Mastocytosis

Lim¹,

Pardanani²,

Tefferi³

2008

Acta Haematol

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“…This mutant is also found in germ cell tumors (9 -11) and in acute myeloid leukemias (7,8). Previous studies have reported the activation of STAT1 or STAT3 by KIT-D816V in transfected cell lines (18,30,44); however, very few have addressed the activation of STAT in neoplastic cells. A noticeable exception is a recent description of STAT5 activation and STAT5 requirement for cell proliferation in HMC-1 cells (19).…”

Section: Discussionmentioning

confidence: 97%

Mechanisms of STAT Protein Activation by Oncogenic KIT Mutants in Neoplastic Mast Cells

Chaix

Lopez

Voisset

et al. 2011

Journal of Biological Chemistry

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“…53 Using chemical inhibitors, it has been suggested that NF-B, mTOR, and PKC␦ are important effectors of KIT D816V . [54][55][56] These hypotheses have not yet been challenged using gene inactivation techniques. Using antisense oligonucleotides and RNA interference, another study very recently implicated the BCL-2-related protein MCL-1 in KIT D816V -dependent cell proliferation.…”

Section: Signaling Downstream Of Kit D816vmentioning

confidence: 99%

“…on May 11, 2018. by guest www.bloodjournal.org From PKC412, 60,63,64 and drugs that target NF-B, 54 mTOR, 56 protein kinase C ␦ (PKC␦), 55 PI3K, 52 and heat shock protein 90 (HSP90). 65 The present study points to FES as a putative target of KIT D816V -mediated cell proliferation.…”

Section: Inhibitors Of Kit D816vmentioning

confidence: 99%

The tyrosine kinase FES is an essential effector of KITD816V proliferation signal

Voisset

Lopez

Dubreuil

et al. 2007

Blood

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KIT is a tyrosine kinase receptor that is aberrantly activated in several neoplasms. In human pathologies, the most frequent mutation of KIT occurs at codon 816. The resulting KIT mutant protein is activated in the absence of ligand and is resistant to the clinically available inhibitors of KIT. In this report, we provide evidence for an essential function of the cytoplasmic tyrosine kinase FES downstream of KIT D816V . FES is phosphorylated on tyrosine residues in cells that carry KIT D816V mutation, and this phosphorylation is KIT dependent. Reduction of FES expression using RNA interference results in decreased cell proliferation in human or murine cells harboring KIT D816V IntroductionThe proto-oncogene c-kit encodes a receptor with tyrosine kinase activity which is essential for hematopoiesis and the development of melanoblasts, germ cells, and interstitial cells of Cajal. Gain-offunction mutations of KIT are implicated in human pathologies. These mutations have been classified as regulatory-type mutations when they affect domains of the receptor necessary for maintaining KIT autoinhibition and structural-type mutations when they directly affect the catalytic domain. Juxtamembrane mutations of KIT are commonly found in gastrointestinal stromal tumors (GISTs), 1 whereas kinase domain mutations are mainly found in mastocytosis, 2 hematologic neoplasms, [3][4][5] and germ-cell tumors. [6][7][8] Very recently, both juxtamembrane and kinase domain mutations of KIT have also been reported in melanomas. 9 The most frequent mutation affects codon 816 in human c-kit cDNA, which corresponds to codon 814 in the homologous mouse sequence. 10 Whereas tyrosine kinase inhibitors such as imatinib are very efficient on wild-type KIT (KIT WT ) and KIT juxtamembrane mutations, KIT D816V is resistant to this treatment. [11][12][13] Therefore, drugs that could target this mutant or an essential downstream effector would be useful tools for the study and the treatment of the associated diseases.Signaling proteins activated downstream of gain-of-function mutants of KIT include many proteins shown previously to participate in wild-type KIT receptor signal transduction. 14,15 They include the classical phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) pathways, as well as a number of signaling proteins activated by many cell-surface receptors such as p38, JNK, VAV, STAT-1, STAT-3, and STAT-5. Activation of PI3K is critical for both WT and mutant KIT in all models studied, while the activation of the mitogen-activated protein (MAP) kinases ERK-1 and ERK-2 appears to be dependent on the cellular context. The importance of each protein or signaling pathway activated downstream of KIT D816V has yet to be fully evaluated.Fps/fes was originally identified as an oncogene from avian (fps) and feline (fes) retroviruses. FES (feline sarcoma) and FER (FES-related) proteins are the only 2 members of a subfamily of cytoplasmic protein tyrosine kinase. 16 FES has been shown to associate with growth factor an...

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PKCδ plays opposite roles in growth mediated by wild-type Kit and an oncogenic Kit mutant

Cited by 15 publications

References 62 publications

<i>KIT</i> and Mastocytosis

<i>KIT</i> and Mastocytosis

Mechanisms of STAT Protein Activation by Oncogenic KIT Mutants in Neoplastic Mast Cells

The tyrosine kinase FES is an essential effector of KITD816V proliferation signal

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