共查询到20条相似文献,搜索用时 31 毫秒
1.
Aamir S. Mukadam Sophia Y. Breusegem Matthew N. J. Seaman 《Cellular and molecular life sciences : CMLS》2018,75(14):2613-2625
The processing of amyloid precursor protein (APP) to the neurotoxic pro-aggregatory Aβ peptide is controlled by the mechanisms that govern the trafficking and localisation of APP. We hypothesised that genes involved in endosomal protein sorting could play an important role in regulating APP processing and, therefore, analysed ~ 40 novel endosome-to-Golgi retrieval genes previously identified in a genome-wide siRNA screen. We report that phospholipase D3 (PLD3), a type II membrane protein, functions in endosomal protein sorting and plays an important role in regulating APP processing. PLD3 co-localises with APP in endosomes and loss of PLD3 function results in reduced endosomal tubules, impaired trafficking of several membrane proteins and reduced association of sortilin-like 1 with APP. 相似文献
2.
Wnt-frizzled signaling to G-protein-coupled effectors 总被引:2,自引:0,他引:2
3.
Hina F. Bhat Marvin E. Adams Firdous A. Khanday 《Cellular and molecular life sciences : CMLS》2013,70(14):2533-2554
Syntrophins are a family of cytoplasmic membrane-associated adaptor proteins, characterized by the presence of a unique domain organization comprised of a C-terminal syntrophin unique (SU) domain and an N-terminal pleckstrin homology (PH) domain that is split by insertion of a PDZ domain. Syntrophins have been recognized as an important component of many signaling events, and they seem to function more like the cell’s own personal ‘Santa Claus’ that serves to ‘gift’ various signaling complexes with precise proteins that they ‘wish for’, and at the same time care enough for the spatial, temporal control of these signaling events, maintaining overall smooth functioning and general happiness of the cell. Syntrophins not only associate various ion channels and signaling proteins to the dystrophin-associated protein complex (DAPC), via a direct interaction with dystrophin protein but also serve as a link between the extracellular matrix and the intracellular downstream targets and cell cytoskeleton by interacting with F-actin. They play an important role in regulating the postsynaptic signal transduction, sarcolemmal localization of nNOS, EphA4 signaling at the neuromuscular junction, and G-protein mediated signaling. In our previous work, we reported a differential expression pattern of alpha-1-syntrophin (SNTA1) protein in esophageal and breast carcinomas. Implicated in several other pathologies, like cardiac dys-functioning, muscular dystrophies, diabetes, etc., these proteins provide a lot of scope for further studies. The present review focuses on the role of syntrophins in membrane targeting and regulation of cellular proteins, while highlighting their relevance in possible development and/or progression of pathologies including cancer which we have recently demonstrated. 相似文献
4.
BAR domain superfamily proteins have emerged as central regulators of dynamic membrane remodeling, thereby playing important
roles in a wide variety of cellular processes, such as organelle biogenesis, cell division, cell migration, secretion, and
endocytosis. Here, we review the mechanistic and structural basis for the membrane curvature-sensing and deforming properties
of BAR domain superfamily proteins. Moreover, we summarize the present state of knowledge with respect to their regulation
by autoinhibitory mechanisms or posttranslational modifications, and their interactions with other proteins, in particular
with GTPases, and with membrane lipids. We postulate that BAR superfamily proteins act as membrane-deforming scaffolds that
spatiotemporally orchestrate membrane remodeling. 相似文献
5.
Signalling roles of mammalian phospholipase D1 and D2 总被引:11,自引:0,他引:11
S. Cockcroft 《Cellular and molecular life sciences : CMLS》2001,58(11):1674-1687
Phospholipase D (PLD) catalyses the hydrolysis of phosphatidylcholine to generate the lipid second messenger, phosphatidate
(PA) and choline. PLD activity in mammalian cells is low and is transiently stimulated upon activation by G-protein-coupled
and receptor tyrosine kinase cell surface receptors. Two mammalian PLD enzymes (PLD1 and PLD2) have been cloned and their
intracellular regulators identified as ARF and Rho proteins, protein kinase Cα as well as the lipid, phosphatidylinositol
[4, 5] bisphosphate (PIP2). I discuss the regulation of these enzymes by cell surface receptors, their cellular localisation and the potential function
of PA as a second messenger. Evidence is presented for a role of PA in regulating the lipid kinase activity of PIP 5-kinase,
an enzyme that synthesises PIP2. A signalling role of phospholipase D via PA and indirectly via PIP2 in regulating membrane traffic and actin dynamics is indicated by the available data.
Received 25 April 2001; received after revision 15 June 2001; accepted 15 June 2001 相似文献
6.
T cell activation is enhanced by the costimulatory interaction of B7 on antigen-presenting cells and CD28 on T cells, resulting
in long-term T cell proliferation, differentiation and production of large amounts of cytokines, such as interleukin (IL)-2.
CTLA-4 is a co-stimulation receptor that shares 31% homology with CD28 and binds B7 family members with higher affinity. CTLA-4
is transiently expressed intracellularly and on the cell surface following activation of T cells. We have studied the kinetics
of CTLA-4 expression and the effects of dexamethasone on CTLA-4 expression during T cell activation in cultures of mouse spleen
cells stimulated by a mixture of immobilized anti-CD3 and anti-CD28 monoclonal antibodies (anti-CD3/CD28 mAb) or concanavalin
A (ConA). CTLA-4 expression peaked on day 2 and returned to background levels after 7 days. Dexamethasone was found to potentiate
CTLA-4 expression in a dose-dependent manner with an EC50 effective concentration 50%) of about 10−8 M. In contrast, other immunosuppressive agents, such as rapamycin or cyclosporin A had no or an inhibitory effect on CTLA-4
expression, respectively. Dexamethasone also stimulated CD28 expression, but inhibited IL-2R expression during anti-CD3/CD28
mAb-induced mouse splenic T cell activation. Western blot analyses of lysates of activated mouse T cells showed that dexamethasone
increased CTLA-4 protein levels twofold during anti-CD3/CD28 mAb-induced activation. Dexamethasone also enhanced CTLA-4 messenger
RNA twofold as quantified by ribonuclease protection assay. The effects of dexamethasone on CTLA-4 expression were glucocorticoid-specific
and completely inhibited by the glucocorticoid receptor antagonist mifepristone (RU486), indicating that the effect of dexamethasone
on CTLA-4 expression is mediated through the glucocorticoid receptor. In conclusion, the immunosuppressive agent dexamethasone
actually stimulates CTLA-4 expression, which is involved in downregulation of T cell activation.
Received 19 May 1999; received after revision 13 July 1999; accepted 13 July 1999 相似文献
7.
Hanna Ungewiß Vera Rötzer Michael Meir Christina Fey Markus Diefenbacher Nicolas Schlegel Jens Waschke 《Cellular and molecular life sciences : CMLS》2018,75(22):4251-4268
Rapidly renewing epithelial tissues such as the intestinal epithelium require precise tuning of intercellular adhesion and proliferation to preserve barrier integrity. Here, we provide evidence that desmoglein 2 (Dsg2), an adhesion molecule of desmosomes, controls cell adhesion and proliferation via epidermal growth factor receptor (EGFR) signaling. Dsg2 is required for EGFR localization at intercellular junctions as well as for Src-mediated EGFR activation. Src binds to EGFR and is required for localization of EGFR and Dsg2 to cell–cell contacts. EGFR is critical for cell adhesion and barrier recovery. In line with this, Dsg2-deficient enterocytes display impaired barrier properties and increased cell proliferation. Mechanistically, Dsg2 directly interacts with EGFR and undergoes heterotypic-binding events on the surface of living enterocytes via its extracellular domain as revealed by atomic force microscopy. Thus, our study reveals a new mechanism by which Dsg2 via Src shapes EGFR function towards cell adhesion. 相似文献
8.
Alvi F Idkowiak-Baldys J Baldys A Raymond JR Hannun YA 《Cellular and molecular life sciences : CMLS》2007,64(3):263-270
The protein kinase C (PKC) family of isoenzymes has been shown to regulate a variety of cellular processes, including receptor
desensitization and internalization, and this has sparked interest in further delineation of the roles of specific isoforms
of PKC in membrane trafficking and endocytosis. Recent studies have identified a novel translocation of PKC to a juxtanuclear
compartment, the pericentrion, which is distinct from the Golgi complex but epicentered on the centrosome. Sustained activation
of PKC (longer than 30 min) also results in sequestration of plasma membrane lipids and proteins to the same compartment,
demonstrating a global effect on endocytic trafficking. This review summarizes these studies, particularly focusing on the
characterization of the pericentrion as a distinct PKC-dependent subset of recycling endosomes. We also discuss emerging insights
into a role for PKC as a central hub in regulating vesicular transport pathways throughout the cell, with implications for
a wide range of pathobiologic processes, e.g. diabetes and abnormal neurotransmission or receptor desensitization.
Received 11 August 2006; received after revision 20 September 2006; accepted 7 November 2006 相似文献
9.
Iber D 《Cellular and molecular life sciences : CMLS》2005,62(2):206-213
Interaction of B cells with membrane antigen results in the formation of the B cell synapse: the B cell receptor (BCR) and antigen concentrate in the contact zone while CD45/B220 and the phosphatase SHP-1 are excluded. This study shows that, unlike in T cells, synapse formation does not require active transport processes (while subsequent antigen extraction and IgM downregulation do). The synapse architecture depends on the available protein ligands in the contact zone. Thus Syk, IgM and Fc receptor accumulation require the presence of ITAM-bearing BCRs, membrane antigen and membrane (IgG-containing) immune complexes, respectively. Remarkably, non-bound proteins are frequently not only homogeneously distributed but excluded from the contact zone. These results suggest that proteins mainly reach the contact zone by undirected diffusion, and in order not to be expelled by molecular crowding they require capture by and fixation to a binding protein.Received 25 August 2004; received after revision 2 November 2004; accepted 17 November 2004 相似文献
10.
Iness Charfi Khaled Abdallah Louis Gendron Graciela Pineyro 《Cellular and molecular life sciences : CMLS》2018,75(12):2257-2271
Soon after internalization delta opioid receptors (DOPrs) are committed to the degradation path by G protein-coupled receptor (GPCR)-associated binding protein. Here we provide evidence that this classical post-endocytic itinerary may be rectified by downstream sorting decisions which allow DOPrs to regain to the membrane after having reached late endosomes (LE). The LE sorting mechanism involved ESCRT accessory protein Alix and the TIP47/Rab9 retrieval complex which supported translocation of the receptor to the TGN, from where it subsequently regained the cell membrane. Preventing DOPrs from completing this itinerary precipitated acute analgesic tolerance to the agonist DPDPE, supporting the relevance of this recycling path in maintaining the analgesic response by this receptor. Taken together, these findings reveal a post-endocytic itinerary where GPCRs that have been sorted for degradation can still recycle to the membrane. 相似文献
11.
Blenn C Wyrsch P Bader J Bollhalder M Althaus FR 《Cellular and molecular life sciences : CMLS》2011,68(8):1455-1466
Oxidative DNA damage to cells activates poly(ADP-ribose)polymerase-1 (PARP-1) and the poly(ADP-ribose) formed is rapidly degraded
to ADP-ribose by poly(ADP-ribose)glycohydrolase (PARG). Here we show that PARP-1 and PARG control extracellular Ca2+ fluxes through melastatin-like transient receptor potential 2 channels (TRPM2) in a cell death signaling pathway. TRPM2 activation
accounts for essentially the entire Ca2+ influx into the cytosol, activating caspases and causing the translocation of apoptosis inducing factor (AIF) from the inner
mitochondrial membrane to the nucleus followed by cell death. Abrogation of PARP-1 or PARG function disrupts these signals
and reduces cell death. ADP-ribose-loading of cells induces Ca2+ fluxes in the absence of oxidative damage, suggesting that ADP-ribose is the key metabolite of the PARP-1/PARG system regulating
TRPM2. We conclude that PARP-1/PARG control a cell death signal pathway that operates between five different cell compartments
and communicates via three types of chemical messengers: a nucleotide, a cation, and proteins. 相似文献
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Kim SH Juhnn YS Kang S Park SW Sung MW Bang YJ Song YS 《Cellular and molecular life sciences : CMLS》2006,63(7-8):930-938
The E5 oncoprotein of human papillomavirus (HPV) 16 plays an important role in early cervical carcinogenesis. Vascular endothelial
growth factor (VEGF) plays a central role in switching on the angiogenic phenotype during early cervical carcinogenesis. However,
the relationship between E5 and VEGF has not previously been examined. To clarify the regulatory role of E5 in VEGF expression,
we transferred the E5 gene into various cell types. E5 increased VEGF expression. The addition of epidermal growth factor
receptor (EGFR) inhibitor significantly suppressed VEGF expression, demonstrating that E5 stimulates VEGF expression through
the activation of EGFR. E5-mediated EGFR activation was accompanied by phosphorylation of Akt and ERK1/2, which are also involved
in VEGF expression. Furthermore, the mRNA stability of VEGF was not affected by E5, but VEGF promoter activity could be modulated
by inhibitors of the EGFR, MEK-ERK1/2 and PI3K/Akt pathways in E5-expressing cells. Collectively, these novel results suggest
that HPV 16 E5 increases VEGF expression by activating EGFR, MEK/ERK1/2 and PI3K/Akt.
Received 23 November 2005; received after revision 10 January 2006; accepted 9 February 2006 相似文献
16.
Biased binding of class IA phosphatidyl inositol 3-kinase subunits to inducible costimulator (CD278)
Acosta YY Zafra MP Ojeda G Bernardone IS Dianzani U Portolés P Rojo JM 《Cellular and molecular life sciences : CMLS》2011,68(18):3065-3079
To better understand T lymphocyte costimulation by inducible costimulator (ICOS; H4; CD278), we analyzed proteins binding
to ICOS peptides phosphorylated at the Y191MFM motif. Phosphorylated ICOS binds class IA phosphatidyl inositol 3-kinase (PI3-K) p85α, p50-55α and p85β regulatory subunits
and p110α, p110δ and p110β catalytic subunits. Intriguingly, T cells expressed high levels of both p110α or p110δ catalytic
subunits, yet ICOS peptides, cell surface ICOS or PI3-kinase class IA regulatory subunits preferentially coprecipitated p110α
catalytic subunits. Silencing p110α or p110δ partially inhibited Akt/PKB activation induced by anti-CD3 plus anti-ICOS antibodies.
However, silencing p110α enhanced and silencing p110δ inhibited Erk activation. Both p110α- and p110δ-specific inhibitors
blocked cytokine secretion induced by TCR/CD3 activation with or without ICOS costimulus, but only p110α inhibitors blocked
ICOS-induced cell elongation. Thus, p110α and p110δ are essential to optimal T cell activation, but their abundance and activity
differentially tune up distinct ICOS signaling pathways. 相似文献
17.
目的探讨CD133基因表达、活化被阻断后对结肠癌干细胞生物学行为的影响。方法从EpcAMhighCD44+结肠癌干细胞中流式分选获得CD133+细胞,感染LV-CD133shRNA载体慢病毒后观察CD133+结肠癌干细胞在生长方式、成球能力、克隆形成率、成瘤能力以及ABCC2mRNA的变化;Westernblot分析CD133-细胞中CD133蛋白表达情况。结果EpcAMhighCD44+结肠癌干细胞中CD133+细胞比例为89.2%。实验组经过LV-CD133shRNA载体病毒感染后,在干细胞养液中细胞改悬浮生长的方式为贴壁生长,不能形成细胞球。MTT法测定发现细胞增殖减慢,克隆形成率明显下降。将感染细胞移植在Balb/C裸鼠体内,在观察期间,感染LV—CD133shRNA载体病毒的CD133+细胞无肿瘤形成。ABCG2mRNA表达水平明显降低(P〈0.01)。从EpcAMhighCD44+结肠癌干细胞中流式分选获得CD133-细胞,其中也有CD133蛋白的表达。结论CD133维持结肠癌干细胞生物学特性。 相似文献
18.
Alvaro Gilsanz Lorena Sánchez-Martín María Dolores Gutiérrez-López Susana Ovalle Yesenia Machado-Pineda Raquel Reyes Guido W. Swart Carl G. Figdor Esther M. Lafuente Carlos Cabañas 《Cellular and molecular life sciences : CMLS》2013,70(3):475-493
ALCAM/CD166 is a member of the immunoglobulin superfamily of cell adhesion molecules (Ig-CAMs) which mediates intercellular adhesion through either homophilic (ALCAM–ALCAM) or heterophilic (ALCAM–CD6) interactions. ALCAM-mediated adhesion is crucial in different physiological and pathological phenomena, with particular relevance in leukocyte extravasation, stabilization of the immunological synapse, T cell activation and proliferation and tumor growth and metastasis. Although the functional implications of ALCAM in these processes is well established, the mechanisms regulating its adhesive capacity remain obscure. Using confocal microscopy colocalization, and biochemical and functional analyses, we found that ALCAM directly associates with the tetraspanin CD9 on the leukocyte surface in protein complexes that also include the metalloproteinase ADAM17/TACE. The functional relevance of these interactions is evidenced by the CD9-induced upregulation of both homophilic and heterophilic ALCAM interactions, as reflected by increased ALCAM-mediated cell adhesion and T cell migration, activation and proliferation. The enhancement of ALCAM function induced by CD9 is mediated by a dual mechanism involving (1) augmented clustering of ALCAM molecules, and (2) upregulation of ALCAM surface expression due to inhibition of ADAM17 sheddase activity. 相似文献
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Vanessa Schmidt Aygul Subkhangulova Thomas E. Willnow 《Cellular and molecular life sciences : CMLS》2017,74(8):1475-1483
Sorting-related receptor with A-type repeats (SORLA) is an intracellular sorting receptor that directs cargo proteins, such as kinases, phosphatases, and signaling receptors, to their correct location within the cell. The activity of SORLA assures proper function of cells and tissues, and receptor dysfunction is the underlying cause of common human malignancies, including Alzheimer’s disease, atherosclerosis, and obesity. Here, we discuss the molecular mechanisms that govern sorting of SORLA and its cargo in multiple cell types, and why genetic defects in this receptor results in devastating diseases. 相似文献