Neoplasia driven by mutant c-KIT is mediated by intracellular, not plasma membrane, receptor signaling

Zhifu Xiang; Frederike Kreisel; Jennifer Cain; AnnaLynn Colson; Michael H Tomasson

doi:10.1128/MCB.01153-06

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Neoplasia driven by mutant c-KIT is mediated by intracellular, not plasma membrane, receptor signaling

Journal article

Peer reviewed

Neoplasia driven by mutant c-KIT is mediated by intracellular, not plasma membrane, receptor signaling

Zhifu Xiang, Frederike Kreisel, Jennifer Cain, AnnaLynn Colson and Michael H Tomasson

Molecular and cellular biology, Vol.27(1), pp.267-282

01/2007

DOI: 10.1128/MCB.01153-06

PMCID: PMC1800644

PMID: 17060458

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https://digitalcommons.wustl.edu/open_access_pubs/2752View

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Abstract

Activating mutations in c-KIT are associated with gastrointestinal stromal tumors, mastocytosis, and acute myeloid leukemia. In attempting to establish a murine model of human KIT(D816V) (hKIT(D816V))-mediated leukemia, we uncovered an unexpected relationship between cellular transformation and intracellular trafficking. We found that transport of hKIT(D816V) protein was blocked at the endoplasmic reticulum in a species-specific fashion. We exploited these species-specific trafficking differences and a set of localization domain-tagged KIT mutants to explore the relationship between subcellular localization of mutant KIT and cellular transformation. The protein products of fully transforming KIT mutants localized to the Golgi apparatus and to a lesser extent the plasma membrane. Domain-tagged KIT(D816V) targeted to the Golgi apparatus remained constitutively active and transforming. Chemical inhibition of intracellular transport demonstrated that Golgi localization is sufficient, but plasma membrane localization is dispensable, for downstream signaling mediated by KIT mutation. When expressed in murine bone marrow, endoplasmic reticulum-localized hKIT(D816V) failed to induce disease in mice, while expression of either Golgi-localized HyKIT(D816V) or cytosol-localized, ectodomain-deleted KIT(D816V) uniformly caused fatal myeloproliferative diseases. Taken together, these data demonstrate that intracellular, non-plasma membrane receptor signaling is sufficient to drive neoplasia caused by mutant c-KIT and provide the first animal model of myelomonocytic neoplasia initiated by human KIT(D816V).

Signal Transduction

Bone Marrow Transplantation

Mutation

Neoplasms - metabolism

Cell Proliferation

Humans

Gene Expression Regulation, Leukemic

Animals

Proto-Oncogene Proteins c-kit - physiology

Female

Golgi Apparatus - metabolism

Proto-Oncogene Proteins c-kit - genetics

Cell Membrane - metabolism

Mice

Mice, Inbred BALB C

Leukemia, Experimental - metabolism

Leukemia, Experimental - genetics

Details

Title: Subtitle: Neoplasia driven by mutant c-KIT is mediated by intracellular, not plasma membrane, receptor signaling
Creators: Zhifu Xiang - Washington University School of Medicine, Campus Box 8007, 660 South Euclid Avenue, St. Louis, MO 63110, USA
Frederike Kreisel
Jennifer Cain
AnnaLynn Colson
Michael H Tomasson
Resource Type: Journal article
Publication Details: Molecular and cellular biology, Vol.27(1), pp.267-282
DOI: 10.1128/MCB.01153-06
PMID: 17060458
PMCID: PMC1800644
NLM abbreviation: Mol Cell Biol
ISSN: 0270-7306
eISSN: 1098-5549
Grant note: P01 CA101937 / NCI NIH HHS P01 CA 101937-01 / NCI NIH HHS
Language: English
Date published: 01/2007
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094317902771

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