共查询到20条相似文献,搜索用时 218 毫秒
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Hiriart E Gruffat H Buisson M Mikaelian I Keppler S Meresse P Mercher T Bernard OA Sergeant A Manet E 《The Journal of biological chemistry》2005,280(44):36935-36945
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Background
The Split ends (Spen) family are large proteins characterised by N-terminal RNA recognition motifs (RRMs) and a conserved SPOC (Spen paralog and ortholog C-terminal) domain. The aim of this study is to characterize the family at the sequence level. 相似文献7.
Ryan L. Stafford 《Journal of molecular biology》2011,412(1):3-13
Calcium/calmodulin-dependent serine protein kinase (CASK) is a conserved multi-domain scaffolding protein involved in brain development, synapse formation, and establishment of cell polarity. To accomplish these diverse functions, CASK participates in numerous protein-protein interactions. In particular, CASK forms competing CASK/Mint1/Velis and CASK/Caskin1/Velis tripartite complexes that physically associate with the cytoplasmic tail of neurexin, a transmembrane protein enriched at presynaptic sites. This study shows that a short linear EEIWVLRK peptide motif from Caskin1 is necessary and sufficient for binding CASK. We also identified the conserved binding site for the peptide on the CASK calmodulin kinase domain. A related EPIWVMRQ peptide from Mint1 was also discovered to be sufficient for binding. Searching all human proteins for the Mint1/Caskin1 consensus peptide ExIWVxR revealed that T-cell lymphoma invasion and metastasis 1 (TIAM1) contains a conserved EEVIWVRRE peptide that was also found to be sufficient for CASK binding in vitro. TIAM1 is well known for its role in tumor metastasis, but it also possesses overlapping cellular and neurological functions with CASK, suggesting a previously unknown cooperation between the two proteins. This new peptide interaction motif also explains how Caskin1 and Mint1 form competing complexes and suggests a new role for the cellular hub protein CASK. 相似文献
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Presynaptic voltage-gated calcium (Ca(2+)) channels mediate Ca(2+) influx into the presynaptic terminal that triggers synaptic vesicle fusion and neurotransmitter release. The immediate proximity of Ca(2+) channels to the synaptic vesicle release apparatus is critical for rapid and efficient synaptic transmission. In a series of biochemical experiments, we demonstrate a specific association of the cytosolic carboxyl terminus of the N-type Ca(2+) channel pore-forming alpha(1B) subunit with the modular adaptor proteins Mint1 and CASK. The carboxyl termini of alpha(1B) bind to the first PDZ domain of Mint1 (Mint1-1). The proline-rich region present in the carboxyl termini of alpha(1B) binds to the SH3 domain of CASK. Mint1-1 is specific for the E/D-X-W-C/S-COOH consensus, which defines a novel class of PDZ domains (class III). The Mint1-1 PDZ domain-binding motif is present only in the "long" carboxyl-terminal splice variants of N-type (alpha(1B)) and P/Q-type (alpha(1A)) Ca(2+) channels, but not in R-type (alpha(1E)) or L-type (alpha(1C)) Ca(2+) channels. Our results directly link presynaptic Ca(2+) channels to a macromolecular complex formed by modular adaptor proteins at synaptic junction and advance our understanding of coupling between cell adhesion and synaptic vesicle exocytosis. 相似文献
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Takayuki Uematsu Kohsuke Tsuchiya Noritada Kobayashi Motoharu Seiki Jun-ichiro Inoue Shuichi Kaneko Takeharu Sakamoto 《Cell death & disease》2021,12(4)
Listeria monocytogenes (LM) infection induces pyroptosis, a form of regulated necrosis, in host macrophages via inflammasome activation. Here, we examined the role of Mint3 in macrophages, which promotes glycolysis via hypoxia-inducible factor-1 activation, during the initiation of pyroptosis following LM infection. Our results showed that Mint3-deficient mice were more resistant to lethal listeriosis than wild-type (WT) mice. Additionally, the mutant mice showed higher levels of IL-1β/IL-18 in the peritoneal fluid during LM infection than WT mice. Moreover, ablation of Mint3 markedly increased the activation of caspase-1, maturation of gasdermin D, and pyroptosis in macrophages infected with LM in vitro, suggesting that Mint3 depletion promotes pyroptosis. Further analyses revealed that Mint3 depletion upregulates inflammasome assembly preceding pyroptosis via glycolysis reduction and reactive oxygen species production. Pharmacological inhibition of glycolysis conferred resistance to listeriosis in a Mint3-dependent manner. Moreover, Mint3-deficient mice treated with the caspase-1 inhibitor VX-765 were as susceptible to LM infection as WT mice. Taken together, these results suggest that Mint3 depletion promotes pyroptosis in host macrophages, thereby preventing the spread of LM infection. Mint3 may serve as a target for treating severe listeriosis by inducing pyroptosis in LM-infected macrophages.Subject terms: Cell death, Infection 相似文献
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Anika Thyrock Martin Stehling Dieter Waschbüsch 《Biochemical and biophysical research communications》2010,396(3):679-38340
In extension to previously applied techniques like yeast two-hybrid and GST pull-down assays, we successfully established a FACS-based FRET analysis to investigate the interaction of the Mint3 adaptor protein and the small Rab GTPase Rab6A in living mammalian cells. A Mint3 mutant containing only the PTB domain (Mint3Δ6) is able to interact with the constitutively active form of Rab6A. Mint3Δ4, a mutant lacking part of the PTB domain was unable to interact with Rab6A in GST pull-down analysis and did not produce FRET signals, when co-expressed with active Rab6A.We demonstrate that this FACS-based FRET analysis is a suitable method for interaction studies between two proteins in living cells. 相似文献
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Yong Zhang Yong-Gang Wang Qi Zhang Xiu-Jie Liu Xuan Liu Li Jiao Wei Zhu Zhao-Huan Zhang Xiao-Lin Zhao Cheng He 《The Journal of biological chemistry》2009,284(18):12469-12479
TrkA receptor signaling is essential for nerve growth factor (NGF)-induced
survival and differentiation of sensory neurons. To identify possible
effectors or regulators of TrkA signaling, yeast two-hybrid screening was
performed using the intracellular domain of TrkA as bait. We identified
muc18-1-interacting protein 2 (Mint2) as a novel TrkA-binding protein and
found that the phosphotyrosine binding domain of Mint2 interacted with TrkA in
a phosphorylation- and ligand-independent fashion. Coimmunoprecipitation
assays showed that endogenous TrkA interacted with Mint2 in rat tissue
homogenates, and immunohistochemical evidence revealed that Mint2 and TrkA
colocalized in rat dorsal root ganglion neurons. Furthermore, Mint2
overexpression inhibited NGF-induced neurite outgrowth in both PC12 and
cultured dorsal root ganglion neurons, whereas inhibition of Mint2 expression
by RNA interference facilitated NGF-induced neurite outgrowth. Moreover, Mint2
was found to promote the retention of TrkA in the Golgi apparatus and inhibit
its surface sorting. Taken together, our data provide evidence that Mint2 is a
novel TrkA-regulating protein that affects NGF-induced neurite outgrowth,
possibly through a mechanism involving retention of TrkA in the Golgi
apparatus.The neurotrophin family member nerve growth factor
(NGF)3 is
essential for proper development, patterning, and maintenance of nervous
systems (1,
2). NGF has two known
receptors; TrkA, a single-pass transmembrane receptor-tyrosine kinase that
binds selectively to NGF, and p75, a transmembrane glycoprotein that binds all
members of the neurotrophin family
(3,
4). NGF binding activates the
kinase domain of TrkA, leading to autophosphorylation
(5). The resulting
phosphotyrosines become docking sites for adaptor proteins involved in signal
transduction pathways that lead to the activation of Ras, Rac,
phosphatidylinositol 3-kinase, phospholipase Cγ, and other effectors
(2,
6). Many of these
TrkA-interacting adaptor proteins have been identified and include, Grb2, APS,
SH2B, fibroblast growth factor receptor substrate 2 (FRS-2), Shc, and human
tumor imaginal disc 1 (TID1)
(7-10).
The identification of these binding partners has contributed greatly to our
understanding of the mechanisms underlying the functional diversity of
NGF-TrkA signaling.Studies have indicated that the transmission of NGF signaling in neurons
involves retrograde transport of NGF-TrkA complexes from the neurite tip to
the cell body
(11-14).
TrkA associates with components of cytoplasmic dynein, and it is thought that
vesicular trafficking of neurotrophins occurs via direct interaction of Trk
receptors with the dynein motor machinery
(14). Furthermore, the
atypical protein kinase C-interacting protein, p62, associates with TrkA and
plays a novel role in connecting receptor signals with the endosomal signaling
network required for mediating TrkA-induced differentiation
(15). Recently, the
membrane-trafficking protein Pincher has been found to mediate
macroendocytosis underlying retrograde signaling by TrkA
(16). Despite the progress
made to date in understanding Trk complex internalization and trafficking, the
mechanisms remain poorly understood.Mint2 (muc18-1-interacting protein 2) belongs to the Mint protein family,
which consists of three members, Mint1, Mint2, and Mint3. Mint proteins were
first identified as interacting proteins of the synaptic vesicle-docking
protein Munc18-1 (17,
18). Mint1 is also sometimes
referred to as mLIN-10, as it is the mammalian orthologue of the
Caenorhabditis elegans LIN-10
(19). Additionally, Mint1,
Mint2, and Mint3 are also referred to as X11α or X11, X11β or X11L
(X11-like), and X11γ or X11L2 (X11-like 2), respectively
(20). All Mint proteins
contain a conserved central phosphotyrosine binding (PTB) domain and two
contiguous C-terminal PDZ domains (repeated sequences in the brain-specific
protein PSD-95, the Drosophila septate junction protein Discs large,
and the epithelial tight junction protein ZO-1)
(17,
18,
21). Mint1 and Mint2 are
expressed only in neuronal tissue
(17), whereas Mint3 is
ubiquitously expressed (18).
Although the function of Mints proteins is not fully clear, their interactions
with the docking and exocytosis factors Mun18 -1 and CASK, ADP-ribosylation
factor (Arf) GTPases involved in vesicle budding
(22), and other synaptic
adaptor proteins, such as neurabin-II/spinophilin
(23), tamalin
(24), and kalirin-7
(25), all suggest possible
roles for Mints in synaptic vesicle docking and exocytosis. Mint proteins have
also been implicated in the trafficking and/or processing of β-amyloid
precursor protein (β-APP). Through their PTB domains, all three Mints
bind to a motif within the cytoplasmic domain of β-APP
(21,
26-29),
and Mint1 and Mint2 can stabilize β-APP, affect β-APP processing,
and inhibit the production and secretion of Aβ
(28,
30-32).
Although the mechanisms by which Mints inhibit β-APP processing are not
yet well known, Mints and their binding partners have emerged as potential
therapeutic targets for the treatment of Alzheimer disease.To uncover new TrkA-interacting factors and gain insight into the
mechanisms that guide TrkA intracellular trafficking and other aspects of TrkA
signaling, we conducted a yeast two-hybrid screen of a brain cDNA library
using the intracellular domain of TrkA as bait. The screen identified several
candidate TrkA-interacting proteins, one of which was Mint2. Follow-up binding
assays showed that the PTB domain of Mint2 alone was necessary and sufficient
for mediating the interaction with TrkA. Endogenous Mint2 was also
coimmunoprecipitated and colocalized with TrkA in rat DRG tissue.
Overexpression and knockdown studies showed that Mint2 could significantly
inhibit NGF-induced neurite outgrowth in both TrkA-expressing PC12 cells and
DRG neurons. Moreover, Mint2 was found to induce the retention of TrkA in the
Golgi apparatus and inhibit its surface sorting. Our results suggest that
Mint2 is a novel regulator of TrkA receptor signaling. 相似文献
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Mint3/X11gamma is an ADP-ribosylation factor-dependent adaptor that regulates the traffic of the Alzheimer's Precursor protein from the trans-Golgi network
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Shrivastava-Ranjan P Faundez V Fang G Rees H Lah JJ Levey AI Kahn RA 《Molecular biology of the cell》2008,19(1):51-64
beta-Amyloid peptides (Abeta) are the major component of plaques in brains of Alzheimer's patients, and are they derived from the proteolytic processing of the beta-amyloid precursor protein (APP). The movement of APP between organelles is highly regulated, and it is tightly connected to its processing by secretases. We proposed previously that transport of APP within the cell is mediated in part through its sorting into Mint/X11-containing carriers. To test our hypothesis, we purified APP-containing vesicles from human neuroblastoma SH-SY5Y cells, and we showed that Mint2/3 are specifically enriched and that Mint3 and APP are present in the same vesicles. Increasing cellular APP levels increased the amounts of both APP and Mint3 in purified vesicles. Additional evidence supporting an obligate role for Mint3 in traffic of APP from the trans-Golgi network to the plasma membrane include the observations that depletion of Mint3 by small interference RNA (siRNA) or mutation of the Mint binding domain of APP changes the export route of APP from the basolateral to the endosomal/lysosomal sorting route. Finally, we show that increased expression of Mint3 decreased and siRNA-mediated knockdowns increased the secretion of the neurotoxic beta-amyloid peptide, Abeta(1-40). Together, our data implicate Mint3 activity as a critical determinant of post-Golgi APP traffic. 相似文献
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The RNA-binding Motif Protein 15B (RBM15B/OTT3) Acts as Cofactor of the Nuclear Export Receptor NXF1
Hiroaki Uranishi Andrei S. Zolotukhin Susan Lindtner Soren Warming Gen-Mu Zhang Jenifer Bear Neal G. Copeland Nancy A. Jenkins George N. Pavlakis Barbara K. Felber 《The Journal of biological chemistry》2009,284(38):26106-26116
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Vishnu S Hertenstein A Betschinger J Knoblich JA Gert de Couet H Fischbach KF 《Developmental biology》2006,289(2):296-307
The Drosophila cell adhesion molecule Rst plays key roles during the development of the embryonic musculature, spacing of ommatidia in the compound eye and of sensory organs on the antenna, as well as in the neuronal wiring of the optic lobe. In rst(CT) mutants lacking the cytoplasmic domain of the Rst protein, cell sorting and apoptosis in the eye are affected, suggesting a requirement of this domain for Rst function. To identify potential interacting proteins, yeast two-hybrid screens were performed using the cytoplasmic domains of Rst and its paralogue Kirre as baits. Among several putative interactors, two paralogous Drosophila PDZ motif proteins related to X11/Mint were identified. X11/Mint family members in C. elegans (LIN-10) and vertebrates are believed to function as adaptor proteins and to regulate the assembly of multi-subunit complexes at the synapse, thereby linking the vesicle cycle to cell adhesion. Using genetic, cell biological, and biochemical approaches, we show that the interaction of Rst with X11Lalpha is of biological significance. The proteins interact, for example, in the context of cell sorting in the pupal retina. 相似文献
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BackgroundRBP-J is involved in number of cellular processes. However, the potential mechanisms of RBP-J on colorectal cancer (CRC) development have not been clearly defined. In this study, we aimed to investigate the role and molecular mechanism of RBP-J in CRC.MethodsThe expression levels of RBP-J and Tiam1 in CRC tissues and cells were evaluated by RT-qPCR or western blot. RBP-J was knocked down with sh-RBP-J or overexpressed by pcDNA3.1-RBP-J in CRC cells. Cell proliferation, migration and invasion abilities were analyzed by MTT, wound healing, and transwell assay, respectively. CHIP-qPCR, RIP and dual luciferase reporter assays were performed to confirm the interaction between miR-182-5p and RBP-J or Tiam1. Expression levels of p-p38 MAPK, p38 MAPK, Slug-1, Twist1 and MMP-9 were analyzed by western blot. G-LISA test was used to detect Rac1 activity.ResultsOur results showed that the expression of RBP-J and Tiam1 was significantly up-regulated in CRC tissues and cells. RBP-J overexpression promoted proliferation, migration and invasion of CRC cells. Moreover, RBP-J was found to directly target miR-182-5p promoter and positively regulate the Tiam1/Rac1/p38 MAPK signaling pathway in CRC cells. It was also proved that miR-182-5p can bind Tiam1 directly. Furthermore, experiments revealed that RBP-J could promote CRC cell proliferation, migration and invasion via miR-182-5p-mediated Tiam1/Rac1/p38 MAPK axis. In addition, knockdown of RBP-J reduced tumor growth and metastasis in CRC mice.ConclusionRBP-J regulates CRC cell growth and metastasis through miR-182-5p mediated Tiam1/Rac1/p38 MAPK signaling pathway, implying potential novel therapeutic targets for CRC patients. 相似文献