RanBPM Is a Phosphoprotein That Associates with the Plasma Membrane and Interacts with the Integrin LFA-1

Denti, Simona; Sirri, Alessandra; Cheli, Alessandra; Rogge, Lars; Innamorati, Giulio; Putignano, Stella; Fabbri, Monica; Pardi, Ruggero; Bianchi, Elisabetta

doi:10.1074/jbc.m313515200

Cited by 90 publications

(137 citation statements)

References 48 publications

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“…All secondary antibodies were purchased from Jackson ImmunoResearch laboratories (West Grove, PA). AntiRanBP9 monoclonal antibody was produced by immunizing mice with a peptide corresponding to 146 -729 amino acids of RanBP9 (10). All antibodies were diluted in 5% fat-free milk in Tris-buffered saline-Tween buffer.…”

Section: Methodsmentioning

confidence: 99%

“…Mouse brain homogenates were prepared in 1% CHAPS buffer and immunoprecipitated with various APP and LRP antibodies. RanBP9 protein was detected by anti-RanBP9 monoclonal antibody (10). As shown in Fig.…”

Section: Endogenous Ranbp9 Interacts With Lrp and App In Brain-mentioning

confidence: 99%

“…RanBP9, also known as RanBPM, acts as a multi-modular scaffolding protein, bridging interactions between the cytoplasmic domains of a variety of membrane receptors and intracellular signaling targets. These include Axl and Sky (8), MET receptor protein-tyrosine kinase (9), and ␤2-integrin LFA-1 (10). Similarly, RanBP9 interacts with Plexin-A receptors to strongly inhibit axonal outgrowth (11) and functions to regulate cell morphology and adhesion (12,13).…”

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confidence: 99%

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Novel Role of RanBP9 in BACE1 Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation

Lakshmana

Yoon

Chen

et al. 2009

Journal of Biological Chemistry

144

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Accumulation of the amyloid ␤ (A␤) peptide derived from the proteolytic processing of amyloid precursor protein (APP) is the defining pathological hallmark of Alzheimer disease. We previously demonstrated that the C-terminal 37 amino acids of lipoprotein receptor-related protein (LRP) robustly promoted A␤ generation independent of FE65 and specifically interacted with Ran-binding protein 9 (RanBP9). In this study we found that RanBP9 strongly increased BACE1 cleavage of APP and A␤ generation. This pro-amyloidogenic activity of RanBP9 did not depend on the KPI domain or the Swedish APP mutation. In cells expressing wild type APP, RanBP9 reduced cell surface APP and accelerated APP internalization, consistent with enhanced ␤-secretase processing in the endocytic pathway. The N-terminal half of RanBP9 containing SPRY-LisH domains not only interacted with LRP but also with APP and BACE1. Overexpression of RanBP9 resulted in the enhancement of APP interactions with LRP and BACE1 and increased lipid raft association of APP. Importantly, knockdown of endogenous RanBP9 significantly reduced A␤ generation in Chinese hamster ovary cells and in primary neurons, demonstrating its physiological role in BACE1 cleavage of APP. These findings not only implicate RanBP9 as a novel and potent regulator of APP processing but also as a potential therapeutic target for Alzheimer disease. The major defining pathological hallmark of Alzheimer disease (AD)2 is the accumulation of amyloid ␤ protein (A␤), a neurotoxic peptide derived from ␤-and ␥-secretase cleavages of the amyloid precursor protein (APP). The vast majority of APP is constitutively cleaved in the middle of the A␤ sequence by ␣-secretase (ADAM10/TACE/ADAM17) in the non-amyloidogenic pathway, thereby abrogating the generation of an intact A␤ peptide. Alternatively, a small proportion of APP is cleaved in the amyloidogenic pathway, leading to the secretion of A␤ peptides (37-42 amino acids) via two proteolytic enzymes, ␤-and ␥-secretase, known as BACE1 and presenilin, respectively (1).The proteolytic processing of APP to generate A␤ requires the trafficking of APP such that APP and BACE1 are brought together in close proximity for ␤-secretase cleavage to occur. We and others have shown that the low density lipoprotein receptor-related protein (LRP), a multifunctional endocytosis receptor (2), binds to APP and alters its trafficking to promote A␤ generation. The loss of LRP substantially reduces A␤ release, a phenotype that is reversed when full-length (LRP-FL) or truncated LRP is transfected in LRP-deficient cells (3, 4). Specifically, LRP-CT lacking the extracellular ligand binding regions but containing the transmembrane domain and the cytoplasmic tail is capable of rescuing amyloidogenic processing of APP and A␤ release in LRP deficient cells (3). Moreover, the LRP soluble tail (LRP-ST) lacking the transmembrane domain and only containing the cytoplasmic tail of LRP is sufficient to enhance A␤ secretion (5). This activity of LRP-ST is achieved by promoting APP/BACE1 intera...

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Section: Methodsmentioning

confidence: 99%

Section: Endogenous Ranbp9 Interacts With Lrp and App In Brain-mentioning

confidence: 99%

mentioning

confidence: 99%

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Novel Role of RanBP9 in BACE1 Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation

Lakshmana

Yoon

Chen

et al. 2009

Journal of Biological Chemistry

144

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“…RanBPM was originally identified as a Ran-GTPase binding protein (21,22). RanBPM is distributed in the nucleus, cytoplasm, plasma membrane and cell junctions (22)(23)(24)(25). RanBPM primarily acts as a scaffolding protein involved in localization of several proteins (24,26).…”

mentioning

confidence: 99%

Stability and Function of Mammalian Lethal Giant Larvae-1 Oncoprotein Are Regulated by the Scaffolding Protein RanBPM

Suresh

Ramakrishna

Kim

et al. 2010

Journal of Biological Chemistry

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The evolutionarily conserved lethal giant larvae (Lgl) tumor suppressor gene has an essential role in establishing apical-basal cell polarity, cell proliferation, differentiation, and tissue organization. However, the precise molecular mechanism by which the Lgl carries out its function remains obscure. In the current study, we have identified Ran-binding protein M (RanBPM) as a novel binding partner of Mgl-1, a mammalian homolog of Drosophila tumor suppressor protein lethal (2) giant larvae (L(2)gl) by yeast two-hybrid screening. RanBPM seems to act as a scaffolding protein with a modulatory function with respect to Mgl-1. The Mgl-1 and RanBPM association was confirmed by co-immunoprecipitation and GST pull-down experiments. Additionally, expression of RanBPM resulted in inhibition of Mgl-1 degradation, and thereby extended the half-life of Mgl-1. Furthermore, the ability of Mgl-1 activity in cell migration and colony formation assay was enhanced by RanBPM. Taken together, our findings reveal that RanBPM plays a novel role in regulating Mgl-1 stability and contributes to its biological function as a tumor suppressor.The lethal giant larvae (Lgl) 2 gene was identified as the first recessive oncogene in Drosophila (1-3). Lgl function is reported to be essential for the development of polarized epithelia (4, 5), localization of cell fate determinant Numb in Drosophila neuroblasts (6, 7) and association with cytoskeletal complex (8). It also has been reported that Lgl prevents tumor formation by antagonizing Decapentaplegic (Dpp) signaling by semaphonrin 5c in the brain (9). Lgl functions in concert with two other tumor suppressor genes: discs large (dlg) and scribble (scrib), primarily involved in maintenance of basolateral membrane domain and basal protein targeting (4, 5, 7). In addition, Lgl functions competitively with Par3 in order to make a complex with Par6-aPKC protein complexes that are crucial for the apical membrane domain (10, 11).Homologs of Lgl have been identified in many species including human, mouse, rat, bovine, insect, worm, slime mold, and yeast (12-15). The two Lgl homologs, Lgl1 and Lgl2 have conserved function in the maintenance of cell polarity and tissue homeostasis. In mouse, changes in Lgl1 activity leads to the loss of apical junctional complex in neuroblasts and hyperplasia (16). Hugl-l, a human homolog of Lgl is strongly down-regulated in malignant melanoma (17). A significant reduction in the expression of Hugl-1 was reported in tumor tissues from colorectal cancer patients. Thus, down-regulation of Hugl-1 correlates with occurrence of colorectal cancers whereas its expression leads to increase in cell adhesion and decreased cell migration (18). Hugl-1 plays a key role in the regulation of proteins, which are involved in epithelial-mesenchymal transition (EMT), a process that enables an epithelial cell to gain mesenchymal and migratory properties (17). In mouse embryonic fibroblasts, a mutant of Mgl-1 lacking five serine residues reduced cell polarization in an in vitro wounding ass...

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“…-RanBPM interacts with the cytoplasmatic domains of a variety of membrane receptors such as integrin β subunit (Denti et al, 2004), c-Met (Wang et al, 2002), LICAM (Cheng et al, 2005), CD39 (Wu et al, 2006) and the calcium channel Cav.3.1. (Kim et al, 2009) to have a major role in regulating cell shape, arrangement, polarity or cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Integrative meta-analysis of protein interaction data identified multiple GID/MRCTLH protein complexes in plants

Miquel¹,

Vicient²

2017

Plant Omics

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GID/MRCTLH is a protein complex involved in the regulation of several cellular processes through the polyubiquitination and proteosome degradation. It has been described in yeast and mammals. Genes coding for homologous proteins are also present in plant genomes but have been little studied. BLAST analyses revealed that genes coding for members of the GID/MRCTLH complex are found in multiple copies in plants, compared to mammals and yeast. The potential structure of the Arabidopsis GID/MRCTLH complex was estimated based on the Arabidopsis protein interaction database Interactome 2.0. According to these data, Arabidopsis may contain two GID/MRCTLH complexes instead of the one described in yeast and mammals. The structure of the two Arabidopsis complexes seem to be similar to the yeast GID complex, and seem to interact with several other proteins out of the complex. These data suggest that, similarly to yeast and mammals, the plant GID/MRCTLH complexes are involved in the regulation of several cellular processes through proteosome protein degradation.

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RanBPM Is a Phosphoprotein That Associates with the Plasma Membrane and Interacts with the Integrin LFA-1

Cited by 90 publications

References 48 publications

Novel Role of RanBP9 in BACE1 Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation

Novel Role of RanBP9 in BACE1 Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation

Stability and Function of Mammalian Lethal Giant Larvae-1 Oncoprotein Are Regulated by the Scaffolding Protein RanBPM

Integrative meta-analysis of protein interaction data identified multiple GID/MRCTLH protein complexes in plants

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