Lysosome-associated protein transmembrane 4α (LAPTM4α) requires two tandemly arranged tyrosine-based signals for sorting to lysosomes

Hogue, Douglas L.; Nash, Colin E.; Ling, Victor; Hobman, Tom C.

doi:10.1042/bj20020205

Cited by 41 publications

(37 citation statements)

References 49 publications

(52 reference statements)

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“…It is a novel protein with a four-membrane-spanning domain and a 55-amino acid COOHterminal region facing the cytoplasm (21). To explore its function, ␤4-tubulin (TUBB4) was revealed as its binding partner from a high-throughput yeast two-hybrid screen, which in turn interacts with C14orf147 (on the ER membrane and involved in MAPK and cytoskeleton), KIAA0746 (in MAPK and Wnt signaling, apoptosis, and focal adhesion) and MGC7036 (associated with phosphatidylinositol signaling; see Supplemental Tables S1 and S4 in Ref.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic islet-specific overexpression of Reg3β protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus

Xiong

Wang

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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. Pancreatic islet-specific overexpression of Reg3␤ protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus. Am J Physiol Endocrinol Metab 300: E669 -E680, 2011. First published January 18, 2011; doi:10.1152/ajpendo.00600.2010.-Reg family proteins have been implicated in islet ␤-cell proliferation, survival, and regeneration. The expression of Reg3␤ (pancreatitis-associated protein) is highly induced in experimental diabetes and acute pancreatitis, but its precise role has not been established. Through knockout studies, this protein was shown to be mitogenic, antiapoptotic, and anti-inflammatory in the liver and pancreatic acinars. To test whether it can promote islet cell growth or survival against experimental damage, we developed ␤-cell-specific overexpression using rat insulin I promoter, evaluated the changes in normal islet function, gene expression profile, and the response to streptozotocin-induced diabetes. Significant and specific overexpression of Reg3␤ was achieved in the pancreatic islets of RIP-I/Reg3␤ mice, which exhibited normal islet histology, ␤-cell mass, and in vivo and in vitro insulin secretion in response to high glucose yet were slightly hyperglycemic and low in islet GLUT2 level. Upon streptozotocin treatment, in contrast to wild-type littermates that became hyperglycemic in 3 days and lost 15% of their weight, RIP-I/Reg3␤ mice were significantly protected from hyperglycemia and weight loss. To identify specific targets affected by Reg3␤ overexpression, a whole genome DNA microarray on islet RNA isolated from the transgenic mice revealed more than 45 genes significantly either up-or downregulated. Among them, isletprotective osteopontin/SPP1 and acute responsive nuclear protein p8/NUPR1 were significantly induced, a result further confirmed by real-time PCR, Western blots, and immunohistochemistry. Our results suggest that Reg3␤ is unlikely an islet growth factor but a putative protector that prevents streptozotocin-induced damage by inducing the expression of specific genes.pancreatitis-associated protein; DNA microarray; real-time polymerase chain reaction; Western blot; immunofluorescence; Reg family proteins; transgenic mice A NORMAL ␤-CELL MASS is a crucial element against the development of diabetes mellitus and is determined by at least four independent parameters, i.e., mitogenic replication, cell size expansion, neogenesis (from other pancreatic cells), and apoptosis (42). The net rate of ␤-cell growth is the balance among the rates of ␤-cell replication, hypertrophy, neogenesis, and apoptosis (10). Various growth factors such as hepatocyte growth factor and glucagon-like peptide-1 (GLP-1) have been reported to stimulate islet cell expansion (12, 13, 43). For a therapeutic purpose, ␤-cell mass could also be supplemented by islet cell transplantation where growth factors were shown to promote the survival and/or expansion of transplanted cells in rodents (8,43). Unfortunately, very few of these factors have been pr...

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Section: Discussionmentioning

confidence: 99%

Pancreatic islet-specific overexpression of Reg3β protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus

Xiong

Wang

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…The cellular expression of LAPTM4A in late endosomes and lysosomes [23] seems to be determined by two tandemly arranged tyrosine-based sorting signals [27]. At tissue level, LAPTM4A is ubiquitarily expressed [28].…”

Section: Discussionmentioning

confidence: 99%

LAPTM4A interacts with hOCT2 and regulates its endocytotic recruitment

Grabner

Brast

Sučić³

et al. 2011

Cell. Mol. Life Sci.

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Human organic cation transporter 2 (hOCT2) is involved in the transport of endogenous and exogenous organic cations mainly in cells of the kidney and the brain. Here, we focus on the regulation of hOCT2 by direct protein-protein interaction. Screening within a mating-based split-ubiquitin-yeast-two-hybrid system (mBSUS) revealed the lysosomal-associated protein transmembrane 4 alpha (LAPTM4A) as a potential interacting protein. Interaction of LAPTM4A and hOCT2 was confirmed by pulldown assays, FRET microscopy analysis and immunofluorescence microscopy. Functionally, overexpression of LAPTM4A significantly decreased ASP(+) uptake in HEK293 cells stably transfected with hOCT2, suggesting a negative regulation of hOCT2-mediated transport. Furthermore, overexpression of LAPTM4A leads to a significantly decreased hOCT2 plasma membrane expression in surface biotinylation experiments. In addition, significant expression of LAPTM4A in human kidney was demonstrated by immunoblotting and immunofluorescence.In this work, LAPTM4A has been identified as interaction partner of hOCT2. LAPTM4A regulates the function of hOCT2 by influencing its trafficking to/from the cell membrane and processing it via the intracellular sorting machinery.

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“…As shown in Figure 7a, alignment of the cytoplasmic tail at the C-terminus of LAPTM4B and that of LAPTM4A revealed three 'YXXF', one 'VL', and one 'LL' motifs. It has been shown recently that two 'YXXF' and one 'VL' motifs within the cytoplasmic tail (Hogue et al, 2002). Therefore, LAPTM4B is likely a lysosome-associated transmembrane protein.…”

Section: Discussionmentioning

confidence: 99%

Molecular cloning and characterization of LAPTM4B, a novel gene upregulated in hepatocellular carcinoma

et al. 2003

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Lysosomal-associated protein transmembrane-4 beta (LAPTM4B), a novel gene upregulated in hepatocellular carcinoma (HCC), was cloned using fluorescence differential display, RACE, and RT-PCR. It contains seven exons and encodes a 35-kDa protein with four putative transmembrane regions. Both the N-and C-termini of the protein are proline-rich, and may serve as potential ligands for the SH3 domain. Immunohistochemical analysis localized the protein predominantly to intracellular membranes. Northern blot showed that the LAPTM4B mRNAs were remarkably upregulated in HCC (87.3%) and correlated inversely with differentiation status. LAPTM4B was also overexpressed in many HCC-derived cell lines. It was also highly expressed in fetal livers and certain adult normal tissues including the heart, skeletal muscle, testis, and ovary. Promoter function assays showed a distinct difference in the gene's activities between BEL7402 and HLE cell lines, suggesting that the transcription factors responsible for regulation of the gene in the two cell lines are different, and that possible negative regulatory cis-elements may exist upstream of the promoter region. It was demonstrated that the N-terminus of LAPTM4B was essential for survival of the cells. Cells harboring the full-length LAPTM4B cDNA expression clone displayed a slightly increased efficiency in colony formation. These results suggest that LAPTM4B is a potential protooncogene, whose overexpression is involved in carcinogenesis and progression of HCC. In normal cells, it may also play important roles such as regulation of cell proliferation and survival.

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Lysosome-associated protein transmembrane 4α (LAPTM4α) requires two tandemly arranged tyrosine-based signals for sorting to lysosomes

Cited by 41 publications

References 49 publications

Pancreatic islet-specific overexpression of Reg3β protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus

Pancreatic islet-specific overexpression of Reg3β protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus

LAPTM4A interacts with hOCT2 and regulates its endocytotic recruitment

Molecular cloning and characterization of LAPTM4B, a novel gene upregulated in hepatocellular carcinoma

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