A Mammalian Lysosomal Membrane Protein Confers Multidrug Resistance upon Expression in Saccharomyces cerevisiae

Hogue, Douglas L.; Kerby, Lilli; Ling, Victor

doi:10.1074/jbc.274.18.12877

Cited by 42 publications

(35 citation statements)

References 61 publications

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“…Here, we report a novel interaction between MCOLN1 and the members of the LAPTM family. Although the cellular function of LAPTMs is not well understood, it has been suggested that LAPTMs might participate in the transport of small molecules across intracellular membranes (Hogue et al, 1996;Hogue et al, 1999). We found that MCOLN1 and LAPTMs colocalize to late endosomes and lysosomes and confirmed the interaction by coimmunoprecipitation in human cells.…”

Section: Introductionsupporting

confidence: 76%

“…Both clones were in-frame with the N-terminal half of ubiquitin. The function of LAPTMs is not completely understood but it has been suggested that they are transporters involved in the subcellular compartmentalization of different compounds (Hogue et al, 1996;Hogue et al, 1999). MCOLN1 protein binding to LAPTMs was confirmed by performing additional yeast twohybrid experiments.…”

Section: Identification Of Laptms As Novel Mcoln1 Binding Partnersmentioning

confidence: 94%

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LAPTMs regulate lysosomal function and interact with mucolipin 1: new clues for understanding mucolipidosis type IV

Vergarajaúregui

Martina

Puertollano

2011

Journal of Cell Science

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SummaryLoss-of-function mutations in mucolipin 1 (MCOLN1) result in mucolipidosis type IV (MLIV), a lysosomal storage disorder characterized by severe mental and psychomotor retardation. MCOLN1 is a lysosomal ion channel that belongs to the transient receptor potential (TRP) superfamily. To better understand the cellular function of MCOLN1, a split-ubiquitin yeast two-hybrid screen was performed with the purpose of revealing new MCOLN1 interaction partners. The screen identified two members of the lysosomeassociated protein transmembrane (LAPTM) family as novel interaction partners of MCOLN1. The binding between MCOLN1 and LAPTM members (LAPTMs) was confirmed by co-immunoprecipitation and yeast two-hybrid assays. In addition, MCOLN1 and LAPTMs extensively colocalize at late endosomes and lysosomes. Overexpression of LAPTM4b caused enlargement of lysosomes and defective lysosomal degradation, indicating that LAPTMs are important for proper lysosomal function. Interestingly, lysosomal swelling induced by LAPTM4b was rescued by expression of MCOLN1, suggesting a functional connection between the two proteins. Finally, depletion of endogenous LAPTMs by siRNA induced accumulation of concentric multi-lamellar structures and electron-dense inclusions that closely resemble the structures found in MLIV cells. Overall, our data provide new insight into the molecular mechanisms of MCOLN1 function and suggest a potential role for LAPTMs in MLIV pathogenesis.

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Section: Introductionsupporting

confidence: 76%

Section: Identification Of Laptms As Novel Mcoln1 Binding Partnersmentioning

confidence: 94%

LAPTMs regulate lysosomal function and interact with mucolipin 1: new clues for understanding mucolipidosis type IV

Vergarajaúregui

Martina

Puertollano

2011

Journal of Cell Science

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“…LAPTM4 was shown previously to transport and sequestrate various small molecules, including nucleosides and antibiotics, into the lysosome, thereby protecting the cell from their harmful effects (5,12,13). This finding suggests that LAPTM5 may also function as an intracellular transporter to the lysosome.…”

Section: Discussionmentioning

confidence: 76%

“…LAPTM5 contains five membrane-spanning segments, three polyproline-tyrosine motifs, and a ubiquitin-interacting motif at its C terminus (33). LAPTM4, structurally related to LAPTM5, was shown previously to transport and sequestrate various small molecules, including nucleosides and antibiotics, into the lysosome, thereby protecting the cell from their harmful effects (5,12,13). Even though the exact function of LAPTM5 remains ill defined, recent studies demonstrated that LAPTM5 is involved in the regulation of antigen receptor expression on the surface of lymphocytes after antigen stimulation (31,32).…”

mentioning

confidence: 99%

A Novel Mechanism for the Autonomous Termination of Pre-B Cell Receptor Expression via Induction of Lysosome-Associated Protein Transmembrane 5

Kawano

Ouchida

Wang

et al. 2012

Molecular and Cellular Biology

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The expression of the pre-B cell receptor (BCR) is confined to the early stage of B cell development, and its dysregulation is associated with anomalies of B-lineage cells, including leukemogenesis. Previous studies suggested that the pre-BCR signal might trigger the autonomous termination of pre-BCR expression even before the silencing of pre-BCR gene expression to prevent sustained pre-BCR expression. However, the underlying mechanism remains ill defined. Here we demonstrate that the pre-BCR signal induces the expression of lysosome-associated protein transmembrane 5 (LAPTM5), which leads to the prompt downmodulation of the pre-BCR. While LAPTM5 induction had no significant impact on the internalization of cell surface pre-BCR, it elicited the translocation of a large pool of intracellular pre-BCR from the endoplasmic reticulum to the lysosomal compartment concomitantly with a drastic reduction of the level of intracellular pre-BCR proteins. This reduction was inhibited by lysosomal inhibitors, indicating the lysosomal degradation of the pre-BCR. Notably, the LAPTM5 deficiency in pre-B cells led to the augmented expression level of surface pre-BCR. Collectively, the pre-BCR induces the prompt downmodulation of its own expression through the induction of LAPTM5, which promotes the lysosomal transport and degradation of the intracellular pre-BCR pool and, hence, limits the supply of pre-BCR to the cell surface.

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“…However, there is no ATP binding sites in the molecular structure of LAPTM4B from bioinformatics analysis. Therefore, it might be less possibility that LAPTM4B-35 itself is a kind of multidrug transporter, despite LAPTM4A is thought to function as a transporter protein (Cabrita et al, 1999;Hogue et al, 1999). Another mechanism for MDR involves in alterations in the apoptotic response associated with PI3K/AKT signaling.…”

Section: Discussionmentioning

confidence: 99%

LAPTM4B: A novel cancer-associated gene motivates multidrug resistance through efflux and activating PI3K/AKT signaling

et al. 2010

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LAPTM4B (lysosomal protein transmembrane 4 beta) is a newly identified cancer-associated gene. Both of its mRNA and the encoded LAPTM4B-35 protein are significantly upregulated with more than 70% frequency in a wide variety of cancers. The LAPTM4B-35 level in cancer is evidenced to be an independent prognostic factor and its upregulation promotes cell proliferation, migration and invasion, as well as tumorigenesis in nude mice. In contrary, knockdown of LAPTM4B-35 expression by RNA interference (RNAi) reverses all of the above malignant phenotypes. We herein reveal a new role of LAPTM4B-35 in promoting multidrug resistance of cancer cells. Upregulation of LAPTM4B-35 motivates multidrug resistance by enhancement of efflux from cancer cells of a variety of chemodrugs with variant structures and properties, including doxorubicin, paclitaxel and cisplatin through colocalization and interaction of LAPTM4B-35 with multidrug resistance (MDR) 1 (P-glycoprotein, P-gp), and also by activation of PI3K/AKT signaling pathway through interaction of PPRP motif contained in the N-terminus of LAPTM4B-35 with the p85a regulatory subunit of PI3K. The specific inhibitors of PI3K and knockdown of LAPTM4B-35 expression by RNAi eliminate the multidrug resistance effect motivated by upregulation of LAPTM4B-35. In conclusion, LAPTM4B-35 motivates multidrug resistance of cancer cells by promoting drug efflux through colocalization and interaction with P-gp, and anti-apoptosis by activating PI3K/AKT signaling. These findings provide a promising novel strategy for sensitizing chemical therapy of cancers and increasing the chemotherapeutic efficacy through knockdown LAPTM4B-35 expression by RNAi.

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A Mammalian Lysosomal Membrane Protein Confers Multidrug Resistance upon Expression in Saccharomyces cerevisiae

Cited by 42 publications

References 61 publications

LAPTMs regulate lysosomal function and interact with mucolipin 1: new clues for understanding mucolipidosis type IV

LAPTMs regulate lysosomal function and interact with mucolipin 1: new clues for understanding mucolipidosis type IV

A Novel Mechanism for the Autonomous Termination of Pre-B Cell Receptor Expression via Induction of Lysosome-Associated Protein Transmembrane 5

LAPTM4B: A novel cancer-associated gene motivates multidrug resistance through efflux and activating PI3K/AKT signaling

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