共查询到20条相似文献,搜索用时 31 毫秒
1.
Tal Hirschhorn Michal Levi-Hofman Oded Danziger Nechama I. Smorodinsky Marcelo Ehrlich 《Cellular and molecular life sciences : CMLS》2017,74(14):2645-2662
The Type-I bone morphogenetic protein receptors (BMPRs), BMPR1A and BMPR1B, present the highest sequence homology among BMPRs, suggestive of functional similitude. However, sequence elements within their extracellular domain, such as signal sequence or N-glycosylation motifs, may result in differential regulation of biosynthetic processing and trafficking and in alterations to receptor function. We show that (i) BMPR1A and the ubiquitous isoform of BMPR1B differed in mode of translocation into the endoplasmic reticulum; and (ii) BMPR1A was N-glycosylated while BMPR1B was not, resulting in greater efficiency of processing and plasma membrane expression of BMPR1A. We further demonstrated the importance of BMPR1A expression and glycosylation in ES-2 ovarian cancer cells, where (i) CRISPR/Cas9-mediated knockout of BMPR1A abrogated BMP2-induced Smad1/5/8 phosphorylation and reduced proliferation of ES-2 cells and (ii) inhibition of N-glycosylation by site-directed mutagenesis, or by tunicamycin or 2-deoxy-d-glucose treatments, reduced biosynthetic processing and plasma membrane expression of BMPR1A and BMP2-induced Smad1/5/8 phosphorylation. 相似文献
2.
SongTing Shi David J. J. de Gorter Willem M. H. Hoogaars Peter A. C. ’t Hoen Peter ten Dijke 《Cellular and molecular life sciences : CMLS》2013,70(3):407-423
Bone morphogenetic proteins (BMPs) are important extracellular cytokines that play critical roles in embryogenesis and tissue homeostasis. BMPs signal via transmembrane type I and type II serine/threonine kinase receptors and intracellular Smad effector proteins. BMP signaling is precisely regulated and perturbation of BMP signaling is connected to multiple diseases, including musculoskeletal diseases. In this review, we will summarize the recent progress in elucidation of BMP signal transduction, how overactive BMP signaling is involved in the pathogenesis of heterotopic ossification and Duchenne muscular dystrophy, and discuss possible therapeutic strategies for treatment of these diseases. 相似文献
3.
Cell surface receptors bind ligands expressed on other cells (in trans) in order to communicate with neighboring cells. However, an increasing number of cell surface receptors are found to also interact with ligands expressed on the same cell (in cis). These observations raise questions regarding the biological role of such cis interactions. Specifically, it is important to know whether cis and trans binding have distinct functional effects and, if so, how a single cell discriminates between interactions in cis versus trans. Further, what are the structural features that allow certain cell surface receptors to engage ligand both on the same as well as on an apposed cell membrane? Here, we summarize known examples of receptors that display cis–trans binding and discuss the emerging diversity of biological roles played by these unconventional two-way interactions, along with their structural basis. 相似文献
4.
Ragno P 《Cellular and molecular life sciences : CMLS》2006,63(9):1028-1037
In this last decade, the structure and functions of the receptor for the urokinase-type plasminogen activator have been extensively
studied and characterized. This interesting receptor plays a key role in cell adhesion, migration and proliferation. It was
identified 20 years ago as the specific cell-surface molecule that could bind and concentrate urokinase on the cell membrane,
thus initiating the proteolytic cascade promoted by the activation of plasminogen. The identification of new extracellular
ligands, such as vitronectin, and of cell-surface interactors, such as integrins and fMet-Leu-Phe receptors, shed new light
on its possible roles, totally independent of the enzymatic properties of its ligand. uPAR ligands and interactors and the
functional consequences of the multiple binding capability of this intriguing receptor are reviewed here.
Received 19 September 2005; received after revision 4 December 2005; accepted 6 December 2005 相似文献
5.
Jean-Leon Thomas Kasey Baker Jinah Han Charles Calvo Harri Nurmi Anne C. Eichmann Kari Alitalo 《Cellular and molecular life sciences : CMLS》2013,70(10):1779-1792
Notch cell interaction mechanism governs cell fate decisions in many different cell contexts throughout the lifetime of all Metazoan species. It links the fate of one cell to that of its neighbors through cell-to-cell contacts, and binding of Notch receptors expressed on one cell to their membrane bound ligands on an adjacent cell. Environmental cues, such as growth factors and extracellular matrix molecules, superimpose a dynamic regulation on this canonical Notch signaling pathway. In this review, we will focus on Notch signaling in the vertebrate vascular and nervous systems and examine its role in angiogenesis, neurogenesis, and neurovascular interactions. We will also highlight the molecular relationships of the Notch pathway with vascular endothelial growth factors (VEGFs) and their high-affinity tyrosine kinase VEGF receptors, key regulators of both angiogenesis and neurogenesis. 相似文献
6.
Mar Orriols Maria Catalina Gomez-Puerto Peter ten Dijke 《Cellular and molecular life sciences : CMLS》2017,74(16):2979-2995
Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive elevation in mean pulmonary arterial pressure. This occurs due to abnormal remodeling of small peripheral lung vasculature resulting in progressive occlusion of the artery lumen that eventually causes right heart failure and death. The most common cause of PAH is inactivating mutations in the gene encoding a bone morphogenetic protein type II receptor (BMPRII). Current therapeutic options for PAH are limited and focused mainly on reversal of pulmonary vasoconstriction and proliferation of vascular cells. Although these treatments can relieve disease symptoms, PAH remains a progressive lethal disease. Emerging data suggest that restoration of BMPRII signaling in PAH is a promising alternative that could prevent and reverse pulmonary vascular remodeling. Here we will focus on recent advances in rescuing BMPRII expression, function or signaling to prevent and reverse pulmonary vascular remodeling in PAH and its feasibility for clinical translation. Furthermore, we summarize the role of described miRNAs that directly target the BMPR2 gene in blood vessels. We discuss the therapeutic potential and the limitations of promising new approaches to restore BMPRII signaling in PAH patients. Different mutations in BMPR2 and environmental/genetic factors make PAH a heterogeneous disease and it is thus likely that the best approach will be patient-tailored therapies. 相似文献
7.
Endomannosidase processes oligosaccharides of α1-antitrypsin and its naturally occurring genetic variants in the Golgi apparatus 总被引:3,自引:0,他引:3
Torossi T Fan JY Sauter-Etter K Roth J Ziak M 《Cellular and molecular life sciences : CMLS》2006,63(16):1923-1932
Endomannosidase provides an alternate glucose-trimming pathway in the Golgi apparatus. However, it is unknown if the action
of endomannosidase is dependent on the conformation of the substrate. We have investigated the processing by endomannosidase
of the α1-antitrypsin oligosaccharides and its disease-causing misfolded Z and Hong Kong variants. Oligosaccharides of wild-type
and misfolded α1-antitrypsin expressed in castanospermine-treated hepatocytes or glucosidase II-deficient Phar 2.7 cells were
selectively processed by endomannosidase and subsequently converted to complex type oligosaccharides as indicated by Endo
H resistance and PNGase F sensitivity. Overexpression of endomannosidase in castanospermine-treated hepatocytes resulted in
processing of all oligosaccharides of wild-type and variants of α1-antitrypsin. Thus, endomannosidase does not discriminate
the folding state of the substrate and provides a back-up mechanism for completion of N-glycosylation of endoplasmic reticulum-escaped glucosylated glycoproteins. For exported misfolded glycoproteins, this would
provide a pathway for the formation of mature oligosaccharides important for their proper trafficking and correct functioning.
Received 18 April 2006; received after revision 12 June 2006; accepted 15 June 2006 相似文献
8.
Dong Gao Ruipeng Wang Bingfeng Li Yongkang Yang Zhonghe Zhai Dan-Ying Chen 《Cellular and molecular life sciences : CMLS》2009,66(15):2573-2584
Toll-like receptors (TLRs) act as sensors of microbial components and elicit innate immune responses. All TLR signaling pathways
activate the nuclear factor-kappaB (NF-κB), which controls the expression of inflammatory cytokine genes. Transforming growth
factor-β-activated kinase 1 (TAK1) is a serine/threonine protein kinase that is critically involved in the activation of NF-κB
by tumor necrosis factor (TNFα), interleukin-1β (IL-1β) and TLR ligands. In this study, we identified a novel protein, WD40
domain repeat protein 34 (WDR34) as a TAK1-interacting protein in yeast two-hybrid screens. WDR34 interacted with TAK1, TAK1-binding
protein 2 (TAB2), TAK1-binding protein 3 (TAB3) and tumor necrosis factor receptor-associated factor 6 (TRAF6) in overexpression
and under physiological conditions. Overexpression of WDR34 inhibited IL-1β-, polyI:C- and lipopolysaccharide (LPS)-induced
but not TNFα-induced NF-κB activation, whereas knockdown of WDR34 by a RNA-interference construct potentiated NF-κB activation
by these ligands. Our findings suggest that WDR34 is a TAK1-associated inhibitor of the IL-1R/TLR3/TLR4-induced NF-κB activation
pathway.
D. Gao and R. Wang contributed equally to this work. 相似文献
9.
Neurotrophins are growth factors implicated in the development and maintenance of different neuronal populations in the nervous system. Neurotrophins bind to two sets of receptors, Trk receptor tyrosine kinases and the p75NTR receptor, to activate several different signaling pathways that mediate various biological functions. While Trk receptor activation has been well-studied and triggers the well-characterized Ras/Rap-MAPK, PI3K-Akt, and PLCgamma-PKC cascades, p75NTR signaling is more complex, and its in vivo significance has not yet been completely determined. In the last few years, p75NTR has received much attention mainly due to recent findings describing pro-neurotrophins as new ligands for the receptor and the ability of the receptor to form different complexes with other transmembrane proteins. This review will update the neurotrophin signaling pathways known for Trk receptors to include newly identified Trk-interacting molecules and will address surprising new findings that suggest a role for p75NTR in different receptor complexes and functions. 相似文献
10.
Zolkiewska A 《Cellular and molecular life sciences : CMLS》2008,65(13):2056-2068
ADAM metalloproteases play important roles in development and disease. One of the key functions of ADAMs is the proteolytic processing of Notch receptors and their ligands. ADAM-mediated cleavage of Notch represents the first step in regulated intramembrane proteolysis of the receptor, leading to activation of the Notch pathway. Recent reports indicate that the transmembrane Notch ligands also undergo ADAM-mediated processing in cultured cells and in vivo. The proteolytic processing of Notch ligands modulates the strength and duration of Notch signals, leads to generation of soluble intracellular domains of the ligands, and may support a bi-directional signaling between cells. 相似文献
11.
Regulation of BMP/Dpp signaling during embryonic development 总被引:9,自引:0,他引:9
12.
A role for <Emphasis Type="Italic">N</Emphasis>-acetylglucosamine as a nutrient sensor and mediator of insulin resistance 总被引:4,自引:0,他引:4
The ability to regulate energy balance at both the cellular and whole body level is an essential process of life. As western
society has shifted to a higher caloric diet and more sedentary lifestyle, the incidence of type 2 diabetes (non-insulin-dependent
diabetes mellitus) has increased to epidemic proportions. Thus, type 2 diabetes has been described as a disease of 'chronic
overnutrition'. There are abundant data to support the relationship between nutrient availability and insulin action. However,
there have been multiple hypotheses and debates as to the mechanism by which nutrient availability modulates insulin signaling
and how excess nutrients lead to insulin resistance. One well-established pathway for nutrient sensing is the hexosamine biosynthetic
pathway (HSP), which produces the acetylated aminosugar nucleotide uridine 5′-diphospho-N-acetylglucosamine (UDP-GlcNAc) as its end product. Since UDP-GlcNAc is the donor substrate for modification of nucleocytoplasmic
proteins at serine and threonine residues with N-acetylglucosamine (O-GlcNAc), the possibility of this posttranslational modification serving as the nutrient sensor has been proposed. We have
recently directly tested this model in adipocytes by examining the effect of elevated levels of O-GlcNAc on insulin-stimulated glucose uptake. In this review, we summarize the existing work that implicates the HSP and O-GlcNAc modification as nutrient sensors and regulators of insulin signaling.
RID="*"
ID="*"Corresponding author. 相似文献
13.
Kysenius K Muggalla P Mätlik K Arumäe U Huttunen HJ 《Cellular and molecular life sciences : CMLS》2012,69(11):1903-1916
The secreted protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipid (LDL) receptor family members LDLR, very low density lipoprotein receptor (VLDLR) and apolipoprotein receptor 2 (ApoER2), and promotes their degradation in intracellular acidic compartments. In the liver, LDLR is a major controller of blood LDL levels, whereas VLDLR and ApoER2 in the brain mediate Reelin signaling, a critical pathway for proper development of the nervous system. Expression level of PCSK9 in the brain is highest in the cerebellum during perinatal development, but is also increased in the adult brain after ischemia. The mechanism of PCSK9 function and its involvement in neuronal apoptosis is poorly understood. We show here that RNAi-mediated knockdown of PCSK9 significantly reduced the death of potassium-deprived cerebellar granule neurons (CGN), as shown by reduced levels of nuclear phosphorylated c-Jun and activated caspase-3, as well as condensed apoptotic nuclei. ApoER2 protein levels were increased in PCSK9 RNAi cells. Knockdown of ApoER2 but not of VLDLR was sufficient to reverse the protection provided by PCSK9 RNAi, suggesting that proapoptotic signaling of PCSK9 is mediated by altered ApoER2 function. Pharmacological inhibition of signaling pathways associated with lipoprotein receptors suggested that PCSK9 regulates neuronal apoptosis independently of NMDA receptor function but in concert with ERK and JNK signaling pathways. PCSK9 RNAi also reduced staurosporine-induced CGN apoptosis and axonal degeneration in the nerve growth factor-deprived dorsal root ganglion neurons. We conclude that PCSK9 potentiates neuronal apoptosis via modulation of ApoER2 levels and related anti-apoptotic signaling pathways. 相似文献
14.
The role of VEGF receptors in angiogenesis; complex partnerships 总被引:6,自引:0,他引:6
Cébe-Suarez S Zehnder-Fjällman A Ballmer-Hofer K 《Cellular and molecular life sciences : CMLS》2006,63(5):601-615
Vascular endothelial growth factors (VEGFs) regulate blood and lymphatic vessel development and homeostasis but also have
profound effects on neural cells. VEGFs are predominantly produced by endothelial, hematopoietic and stromal cells in response
to hypoxia and upon stimulation with growth factors such as transforming growth factors, interleukins or platelet-derived
growth factor. VEGFs bind to three variants of type III receptor tyrosine kinases, VEGF receptor 1, 2 and 3. Each VEGF isoform
binds to a particular subset of these receptors giving rise to the formation of receptor homo- and heterodimers that activate
discrete signaling pathways. Signal specificity of VEGF receptors is further modulated upon recruitment of coreceptors, such
as neuropilins, heparan sulfate, integrins or cadherins. Here we summarize the knowledge accumulated since the discovery of
these proteins more than 20 years ago with the emphasis on the signaling pathways activated by VEGF receptors in endothelial
cells during cell migration, growth and differentiation.
Received 15 September 2005; received after revision 11 November; accepted 24 November 2005 相似文献
15.
Bidart M Ricard N Levet S Samson M Mallet C David L Subileau M Tillet E Feige JJ Bailly S 《Cellular and molecular life sciences : CMLS》2012,69(2):313-324
Bone Morphogenetic Protein 9 (BMP9) has been recently found to be the physiological ligand for the activin receptor-like kinase
1 (ALK1), and to be a major circulating vascular quiescence factor. Moreover, a soluble chimeric ALK1 protein (ALK1-Fc) has
recently been developed and showed powerful anti-tumor growth and anti-angiogenic effects. However, not much is known concerning
BMP9. This prompted us to investigate the human endogenous sources of this cytokine and to further characterize its circulating
form(s) and its function. Analysis of BMP9 expression reveals that BMP9 is produced by hepatocytes and intrahepatic biliary
epithelial cells. Gel filtration analysis combined with ELISA and biological assays demonstrate that BMP9 circulates in plasma
(1) as an unprocessed inactive form that can be further activated by furin a serine endoprotease, and (2) as a mature and
fully active form (composed of the mature form associated with its prodomain). Analysis of BMP9 circulating levels during
mouse development demonstrates that BMP9 peaks during the first 3 weeks after birth and then decreases to 2 ng/mL in adulthood.
We also show that circulating BMP9 physiologically induces a constitutive Smad1/5/8 phosphorylation in endothelial cells.
Taken together, our results argue for the role of BMP9 as a hepatocyte-derived factor, circulating in inactive (40%) and active
(60%) forms, the latter constantly activating endothelial cells to maintain them in a resting state. 相似文献
16.
A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2 总被引:1,自引:0,他引:1
Cébe Suarez S Pieren M Cariolato L Arn S Hoffmann U Bogucki A Manlius C Wood J Ballmer-Hofer K 《Cellular and molecular life sciences : CMLS》2006,63(17):2067-2077
The development of functional blood and lymphatic vessels requires spatio-temporal coordination of the production and release
of growth factors such as vascular endothelial growth factors (VEGFs). VEGF family proteins are produced in multiple isoforms
with distinct biological properties and bind to three types of VEGF receptors. A VEGF-A splice variant, VEGF-A165b, has recently been isolated from kidney epithelial cells. This variant is identical to VEGF-A165 except for the last six amino acids encoded by an alternative exon. VEGF-A165b and VEGF-A165 bind VEGF receptors 1 and 2 with similar affinity. VEGF-A165b elicits drastically reduced activity in angiogenesis assays and even counteracts signaling by VEGF-A165. VEGF-A165b weakly binds to heparan sulfate and does not interact with neuropilin-1, a coreceptor for VEGF receptor 2. To determine
the molecular basis for altered signaling by VEGF-A165b we measured VEGF receptor 2 and ERK kinase activity in endothelial cells in culture. VEGF-A165 induced strong and sustained activation of VEGF receptor 2 and ERK-1 and −2, while activation by VEGF-A165b was only weak and transient. Taken together these data show that VEGF-A165b has attenuated signaling potential through VEGF receptor 2 defining this new member of the VEGF family as a partial receptor
agonist.
Received 31 May 2006; received after revision 26 June 2006; accepted 14 July 2006 相似文献
17.
Dependence receptors: between life and death 总被引:2,自引:0,他引:2
The recently described family of dependence receptors is a new family of functionally related receptors.
These proteins have little sequence similarity but display the common feature of inducing two completely opposite
intracellular signals depending on ligand availability: in the presence of ligand, these receptors transduce a
positive signal leading to survival, differentiation or migration, while in the absence of ligand, the receptors
initiate or amplify a negative signal for apoptosis. Thus, cells that express these proteins manifest a state of
dependence on their respective ligands. The mechanisms that trigger cell death induction in the absence of ligand
are in large part unknown, but typically require cleavage by specific caspases. In this review we will present the
proposed mechanisms for cell death induction by these receptors and their potential function in nervous system
development and regulation of tumorigenesis.Received 19 December 2003; received after revision 19 February 2004; accepted 26 February 2004 相似文献
18.
Nikita Minhas Meilang Xue Christopher J. Jackson 《Cellular and molecular life sciences : CMLS》2017,74(10):1895-1906
Activated protein C (APC) is a natural anticoagulant with strong anti-inflammatory, anti-apoptotic, and barrier stabilizing properties. These cytoprotective properties of APC are thought to be exerted through its pathway involving the binding of APC to endothelial protein C receptor and cleavage of protease-activated receptors. In this study, we found that APC enhanced endothelial barrier integrity via a novel pathway, by binding directly to and activating Tie2, a transmembrane endothelial tyrosine kinase receptor. Binding assays demonstrated that APC competed with the only known ligands of Tie2, the angiopoietins (Angs). APC bound directly to Tie2 (Kd ~3 nM), with markedly stronger binding affinity than Ang2. After binding, APC rapidly activated Tie2 to enhance endothelial barrier function as shown by Evan’s blue dye transfer across confluent cell monolayers and in vivo studies. Blocking Tie2 restricted endothelial barrier integrity. This study highlights a novel mechanism by which APC binds directly to Tie2 to enhance endothelial barrier integrity, which helps to explain APC’s protective effects in vascular leakage-related pathologies. 相似文献
19.
Pinho SS Seruca R Gärtner F Yamaguchi Y Gu J Taniguchi N Reis CA 《Cellular and molecular life sciences : CMLS》2011,68(6):1011-1020
Several mechanisms have been proposed to explain the E-cadherin dysfunction in cancer, including genetic and epigenetic alterations.
Nevertheless, a significant number of human carcinomas have been seen that show E-cadherin dysfunction that cannot be explained
at the genetic/epigenetic level. A substantial body of evidence has appeared recently that supports the view that other mechanisms
operating at the post-translational level may also affect E-cadherin function. The present review addresses molecular aspects
related to E-cadherin N-glycosylation and evidence is presented showing that the modification of N-linked glycans on E-cadherin can affect the adhesive function of this adhesion molecule. The role of glycosyltransferases
involved in the remodeling of N-glycans on E-cadherin, including N-acetylglucosaminyltransferase III (GnT-III), N-acetylglucosaminyltransferase V (GnT-V), and the α1,6 fucosyltransferase (FUT8) enzyme, is also discussed. Finally, this
review discusses an alternative functional regulatory mechanism for E-cadherin operating at the post-translational level, N-glycosylation, that may underlie the E-cadherin dysfunction in some carcinomas. 相似文献
20.
Zafirova B Wensveen FM Gulin M Polić B 《Cellular and molecular life sciences : CMLS》2011,68(21):3519-3529
NKG2D is one of the most intensively studied immune receptors of the past decade. Its unique binding and signaling properties,
expression pattern, and functions have been attracting much interest within the field due to its potent antiviral and anti-tumor
properties. As an activating receptor, NKG2D is expressed on cells of the innate and adaptive immune system. It recognizes
stress-induced MHC class I-like ligands and acts as a molecular sensor for cells jeopardized by viral infections or DNA damage.
Although the activating functions of NKG2D have been well documented, recent analysis of NKG2D-deficient mice suggests that
this receptor may have a regulatory role during NK cell development. In this review, we will revisit known aspects of NKG2D
functions and present new insights in the proposed influence of this molecule on hematopoietic differentiation. 相似文献