Rab27b regulates c-kit expression by controlling the secretion of stem cell factor

Tanaka, Chika; Kaji, Hiroaki; He, Jing; Hazama, Ryoichi; Yokoyama, Kunio; Kinoshita, Emi; Tsujioka, Takayuki; Tohyama, Kaoru; Yamamura, Hirohei; Nishio, Hisahide; Tohyama, Yumi

doi:10.1016/j.bbrc.2012.02.030

Cited by 6 publications

(5 citation statements)

References 30 publications

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“…Depletion of Rab27b has previously been suggested to reduce surface expression of c-kit in megakaryocytes [27]. To rule out the possibility that deficiency of Rab27b might impair chemokine receptor expression, we analyzed CXCR2 (receptor for MIP-2) expression on wild-type, Rab27b KO and Rab27DKO BMDN by flow cytometry.…”

Section: Resultsmentioning

confidence: 99%

A role for Rab27 in neutrophil chemotaxis and lung recruitment

et al. 2014

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BackgroundNeutrophils are a critical part of the innate immune system. Their ability to migrate into infected or injured tissues precedes their role in microbial killing and clearance. We have previously shown that Rab27a can promote neutrophil migration by facilitating uropod release through protease secretion from primary granule exocytosis at the cell rear. Rab27b has been implicated in primary granule exocytosis but its role in neutrophil migration has not been investigated.ResultsHere we found Rab27b to be expressed in bone marrow derived neutrophils and Rab27b knockout (Rab27b KO) along with Rab27a/b double knockout (Rab27DKO) neutrophils exhibited impaired transwell migration in vitro in response to chemokines MIP-2 and LTB4. Interestingly, no additional defect in migration was observed in Rab27DKO neutrophils compared with Rab27b KO neutrophils. In vivo, Rab27DKO mice displayed severe impairment in neutrophil recruitment to the lungs in a MIP-2 dependent model but not in an LPS dependent model.ConclusionsThese data taken together implicate Rab27b in the regulation of neutrophil chemotaxis, likely through the regulation of primary granule exocytosis.

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Section: Resultsmentioning

confidence: 99%

A role for Rab27 in neutrophil chemotaxis and lung recruitment

et al. 2014

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“…Notably, RAB27B depletion significantly blunted the growth of TF-1 DKO cells ( Figure 3C ), but not the growth of parental TF-1 cells ( Supplemental Figure 3A ). RAB27B is reported to be involved in exosomes and in cytokine secretion ( 30 , 31 ). However, our data suggest that RAB27B depletion does not affect exosome secretion in TF-1–DKO cells ( Supplemental Figure 4A ).…”

Section: Resultsmentioning

confidence: 99%

RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia

Ren¹,

Xing²,

Lv³

et al. 2023

Journal of Clinical Investigation

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RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2- mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL -deficient or NRAS -mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS–mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers.

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“…To inhibit CH25H gene expression, a vector for short-hairpin RNA (shRNA) against CH25H incorporated in pLKO.1-puro (Sigma-Aldrich, Mission shRNA code: TRCN115963) was transfected into HL-60 and MDS-L cells by ViraPower lentiviral Directional TOPO Expression kit (Invitrogen) 37 and positive clones were selected with 2 μg/ml puromycin. Likewise, we introduced the control vector (Sigma-Aldrich, Mission TurboGFP TM shRNA Control Vector) into HL-60 and MDS-L cells.…”

Section: Methodsmentioning

confidence: 99%

Five-aza-2′-deoxycytidine-induced hypomethylation of cholesterol 25-hydroxylase gene is responsible for cell death of myelodysplasia/leukemia cells

Tsujioka¹,

Yokoi²,

Itano³

et al. 2015

Sci Rep

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DNA methyltransferase inhibitors (DNMT inhibitors) are administered for high-risk MDS, but their action mechanisms are not fully understood. Hence, we performed a genome-wide DNA methylation assay and focused on cholesterol 25-hydroxylase (CH25H) among the genes whose expression was up-regulated and whose promoter region was hypomethylated after decitabine (DAC) treatment in vitro. CH25H catalyzes hydroxylation of cholesterol and produces 25-hydroxycholesterol (25-OHC). Although CH25H mRNA expression level was originally low in MDS/leukemia cell lines, exposure to DNMT inhibitors enhanced CH25H mRNA expression. The promoter region of CH25H was originally hypermethylated in HL-60 and MDS-L cells, but DAC treatment induced their hypomethylation together with increased CH25H mRNA expression, activation of CH25H-oxysterol pathway, 25-OHC production and apoptotic cell death. We further confirmed that normal CD34-positive cells revealed hypomethylated status of the promoter region of CH25H gene. CH25H-knockdown by transfection of shRNA lentiviral vector into the cell lines partially protected the cells from DAC-induced cell death. Exogenous addition of 25-OHC suppressed leukemic cell growth. The present study raises a possibility that DNMT inhibitors activate CH25H-oxysterol pathway by their hypomethylating mechanism and induce leukemic cell death. Further investigations of the promoter analysis of CH25H gene and therapeutic effects of DNMT inhibitors on MDS/leukemia will be warranted.

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Rab27b regulates c-kit expression by controlling the secretion of stem cell factor

Cited by 6 publications

References 30 publications

A role for Rab27 in neutrophil chemotaxis and lung recruitment

A role for Rab27 in neutrophil chemotaxis and lung recruitment

RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia

Five-aza-2′-deoxycytidine-induced hypomethylation of cholesterol 25-hydroxylase gene is responsible for cell death of myelodysplasia/leukemia cells

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