共查询到20条相似文献,搜索用时 31 毫秒
1.
Nerve growth factor: structure and function 总被引:13,自引:0,他引:13
Neurotrophins are critical for the development and maintenance of the peripheral and central nervous system. These highly homologous, homodimeric growth factors control cell survival, differentiation, growth cessation, and apoptosis of sensory neurons. The biological functions of the neurotrophins are mediated through two classes of cell surface receptors, the Trk receptors and the p75 neurotrophin receptor (p75NTR). Nerve growth factor (NGF), the best characterized member of the neurotrophin family, sends its survival signals through activation of TrkA and can induce cell death by binding to p75NTR. Recent domain deletion and mutagenesis studies have identified the membrane-proximal domain of the Trks as necessary and sufficient for ligand binding. Crystal structures of this domain of TrkA, TrkB, and TrkC, and an alanine scanning analysis of this domain of TrkA and TrkC have allowed identification of the ligand-binding site. The recent crystal structure of the complex between NGF and the ligand-binding domain of TrkA defines the orientation of NGF in the signaling complex, and eludicates the structural basis for binding and specificity in the family. Further structural work on NGF-TrkA-p7SNTR complexes will be necessary to address the many remaining questions in this complex signaling system. 相似文献
2.
The neurotrophins, a class of four related growth factors, utilize a dual receptor system consisting of Trk receptor tyrosine kinases and the structurally unrelated p75(NTR) to modulate diverse and sometimes opposing biological actions. The identification of novel ligands for p75(NTR), unconventional mechanisms for Trk activation and unique signaling intermediates further underscores the complex nature of neurotrophin: receptor interactions, as well as their functions within and outside of the nervous systems. This review summarizes recent surprises of how ligand-receptor pairing may affect diverse developmental events, regulate response to injury and extend their influence on memory and learning. 相似文献
3.
Neurotrophin signalling pathways regulating neuronal apoptosis 总被引:18,自引:0,他引:18
Recent evidence indicates that naturally occurring neuronal death in mammals is regulated by the interplay between receptor-mediated prosurvival and proapoptotic signals. The neurotrophins, a family of growth factors best known for their positive effects on neuronal biology, have now been shown to mediate both positive and negative survival signals, by signalling through the Trk and p75 neurotrophin receptors, respectively. The mechanisms whereby these two neurotrophin receptors interact to determine neuronal survival have been difficult to decipher, largely because both can signal independently or coincidentally, depending upon the cell or developmental context. Nonetheless, the past several years have seen significant advances in our understanding of this receptor signalling system. In this review, we focus on the proapoptotic actions of the p75 neurotrophin receptor (p75NTR), and on the interplay between Trk and p75NTR that determines neuronal survival. 相似文献
4.
Elisa Tomellini Chann Lagadec Renata Polakowska Xuefen Le Bourhis 《Cellular and molecular life sciences : CMLS》2014,71(13):2467-2481
p75NTR, the common receptor for both neurotrophins and proneurotrophins, has been widely studied because of its role in many tissues, including the nervous system. More recently, a close relationship between p75NTR expression and pluripotency has been described. p75NTR was shown to be expressed in various types of stem cells and has been used to prospectively isolate stem cells with different degrees of potency. Here, we give an overview of the current knowledge on p75NTR in stem cells, ranging from embryonic to adult stem cells, and cancer stem cells. In an attempt to address its potential role in the control of stem cell biology, the molecular mechanisms underlying p75NTR signaling in different models are also highlighted. p75NTR-mediated functions include survival, apoptosis, migration, and differentiation, and depend on cell type, (pro)neurotrophin binding, interacting transmembrane co-receptors expression, intracellular adaptor molecule availability, and post-translational modifications, such as regulated proteolytic processing. It is therefore conceivable that p75NTR can modulate cell-fate decisions through its highly ramified signaling pathways. Thus, elucidating the potential implications of p75NTR activity as well as the underlying molecular mechanisms of p75NTR will shed new light on the biology of both normal and cancer stem cells. 相似文献
5.
Smrcka AV 《Cellular and molecular life sciences : CMLS》2008,65(14):2191-2214
G protein betagamma subunits are central participants in G protein-coupled receptor signaling pathways. They interact with receptors, G protein alpha subunits and downstream targets to coordinate multiple, different GPCR functions. Much is known about the biology of Gbetagamma subunits but mysteries remain. Here, we will review what is known about general aspects of structure and function of Gbetagamma as well as discuss emerging mechanisms for regulation of Gbetagamma signaling. Recent data suggest that Gbetagamma is a potential therapeutic drug target. Thus, a thorough understanding of the molecular and physiological functions of Gbetagamma has significant implications. 相似文献
6.
Marine Baptissart Aurelie Vega Emmanuelle Martinot Silvère Baron Jean-Marc A. Lobaccaro David H. Volle 《Cellular and molecular life sciences : CMLS》2013,70(23):4511-4526
Bile acids are cholesterol metabolites that have been extensively studied in recent decades. In addition to having ancestral roles in digestion and fat solubilization, bile acids have recently been described as signaling molecules involved in many physiological functions, such as glucose and energy metabolisms. These signaling pathways involve the activation of the nuclear receptor farnesoid X receptor (FXRα) or of the G protein-coupled receptor TGR5. In this review, we will focus on the emerging role of FXRα, suggesting important functions for the receptor in steroid metabolism. It has been described that FXRα is expressed in the adrenal glands and testes, where it seems to control steroid production. FXRα also participates in steroid catabolism in the liver and interferes with the steroid signaling pathways in target tissues via crosstalk with steroid receptors. In this review, we discuss the potential impacts of bile acid (BA), through its interactions with steroid metabolism, on glucose metabolism, sexual function, and prostate and breast cancers. Although several of the published reports rely on in vitro studies, they highlight the need to understand the interactions that may affect health. This effect is important because BA levels are increased in several pathophysiological conditions related to liver injuries. Additionally, BA receptors are targeted clinically using therapeutics to treat liver diseases, diabetes, and cancers. 相似文献
7.
C. L. Salanga M. O’Hayre T. Handel 《Cellular and molecular life sciences : CMLS》2009,66(8):1370-1386
Chemokines are small, secreted proteins that bind to the chemokine receptor subfamily of class A G protein-coupled receptors.
Collectively, these receptor-ligand pairs are responsible for diverse physiological responses including immune cell trafficking,
development and mitogenic signaling, both in the context of homeostasis and disease. However, chemokines and their receptors
are not isolated entities, but instead function in complex networks involving homo- and heterodimer formation as well as crosstalk
with other signaling complexes. Here the functional consequences of chemokine receptor activity, from the perspective of both
direct physical associations with other receptors and indirect crosstalk with orthogonal signaling pathways, are reviewed.
Modulation of chemokine receptor activity through these mechanisms has significant implications in physiological and pathological
processes, as well as drug discovery and drug efficacy. The integration of signals downstream of chemokine and other receptors
will be key to understanding how cells fine-tune their response to a variety of stimuli, including therapeutics.
Received 19 October 2008; received after revision 7 November 2008; accepted 11 November 2008
C. L. Salanga, M. O’Hayre: These authors contributed equally. 相似文献
8.
Lysophospholipids have long been recognized as membrane phospholipid metabolites, but only recently has their role as intercellular
signaling molecules been appreciated. Two of the best-studied lysophospholipids, LPA and S1P, signal through cognate G-protein-coupled
receptors to activate many well-known intracellular signaling pathways, leading to a variety of biologically important cell
responses. Lysophospholipids and their receptors have been found in a wide range of tissues and cell types, indicating their
importance in many physiological processes, including reproduction, vascular development, cancer and nervous system function.
This article will focus on the most recent findings regarding the biological functions of lysophospholipids in mammalian systems,
specifically as they relate to health and disease.
Received 5 April 2006; received after revision 22 June 2006; accepted 9 August 2006 相似文献
9.
Davoli C Marconi A Serafino A Iannoni C Marcheggiano A Ravagnan G 《Cellular and molecular life sciences : CMLS》2002,59(3):527-539
Nerve growth factor (NGF) belongs by sequence homology to the neurotrophins, a family of proteins binding the same p75 receptor
and closely related members of the Trk family of receptor tyrosine kinases. Fundamental in the vertebrate nervous system,
neurotrophin signals have also been suggested as essential for relatively complex nervous systems occurring in invertebrate
species that live longer than Caenorhabditis elegans and Drosophila melanogaster. Mammalian neurotrophins have been found to influence invertebrate neuronal growth. However, there are only a few data on
the presence of molecules related to neurotrophin signalling components in invertebrates. Our studies provide evidence that
analogues of neurotrophins and neurotrophin receptors are expressed in Eisenia foetida earthworms. In particular, NGF-like and Trk-like immunoreactive proteins are both expressed in the nervous system, whereas
p75-like positivity identifies tubular structures associated with dorsal pores that are involved in the earthworm response
to mechanical irritation or stress.
Received 12 November 2001; received after revision 8 January 2002; accepted 8 January 2002 相似文献
10.
Receptor binding, internalization, and retrograde transport of neurotrophic factors 总被引:15,自引:0,他引:15
This review deals with the receptor interactions of neurotrophic factors, focusing on the neurotrophins of the nerve growth
factor (NGF) family, the glial cell derived neurotrophic factor (GDNF) family, and the ciliary neurotrophic factor (CNTF)
family. The finding that two proteins, p75NTR and Trk, act as receptors for NGF in neurons generated the discovery of other neurotrophic factors/receptor families and
has enhanced our understanding of the development, survival, regeneration, and degeneration of the nervous system. The kinetics
of binding, the structure of the ligand-receptor complex, and the mechanism of retrograde transport of the neurotrophins are
discussed in detail and compared to information available on the GDNF and CNTF families. Each neurotrophic factor family,
i.e., NGF, GDNF, and CNTF, has a set of receptors with specificity for individual members of the family and a common receptor
without member specificity that, in some families, generates the cellular signal and retrograde transport. 相似文献
11.
12.
Lysophosphatidic acid: receptors, signaling and survival 总被引:8,自引:0,他引:8
Though the mitogenic activity of lysophosphatidic acid (LPA) has been well established through classical studies, its mechanism of action was long obscure. Recent identification and cloning of LPA-specific receptors has led to the elucidation of the G-proteins and signaling pathways through which this molecule functions. In addition to its mitogenic properties, recent reports have suggested that LPA may also promote cell survival. This review will summarize the current literature regarding LPA signaling and its role as an antiapoptotic factor. 相似文献
13.
Neuronal signaling and the regulation of bone remodeling 总被引:5,自引:0,他引:5
Elefteriou F 《Cellular and molecular life sciences : CMLS》2005,62(19-20):2339-2349
An increasing number of studies suggest that nerve-derived signals play an important role in the regulation of bone remodeling. Neuropeptides and receptors/transporters of adrenergic, glutaminergic, serotoninergic, dopaminergic and sensory nature have been described in osteoblasts in vitro. Downstream signaling pathways and targets genes have been identified, but the in vivo relevance of these findings remained controversial until more recent gene gain and loss of function studies confirmed the role of CGRP and beta2-adrenergic receptor signaling in osteoblasts. Tissue and time-conditional mutant mice originally generated for studies unrelated to bone are now available tools to determine the role of neuronal signaling in bone and to dissociate the central and peripheral role of these signals. Lastly, understanding how the central nervous system integrates homeostatic signals with the regulation of bone homeostasis will be the next exciting subject of research in the field. 相似文献
14.
15.
TNF-related apoptosis-inducing ligand (TRAIL) is a prominent cytokine capable of inducing apoptosis. It can bind to five different cognate receptors, through which diverse intracellular pathways can be activated. TRAIL’s ability to preferentially kill transformed cells makes it a promising potential weapon for targeted tumor therapy. However, recognition of several resistance mechanisms to TRAIL-induced apoptosis has indicated that a thorough understanding of the details of TRAIL biology is still essential before this weapon can be confidently unleashed. Critical to this aim is revealing the functions and regulation mechanisms of TRAIL’s potent death receptor DR5. Although expression and signaling mechanisms of DR5 have been extensively studied, other aspects, such as its subcellular localization, non-signaling functions, and regulation of its membrane transport, have only recently attracted attention. Here, we discuss different aspects of TRAIL/DR5 biology, with a particular emphasis on the factors that seem to influence the cell surface expression pattern of DR5, along with factors that lead to its nuclear localization. Disturbance of this balance apparently affects the sensitivity of cancer cells to TRAIL-mediated apoptosis, thus constituting an eligible target for potential new therapeutic agents. 相似文献
16.
Latha Ramalingam Eunjin Oh Debbie C. Thurmond 《Cellular and molecular life sciences : CMLS》2013,70(16):2815-2834
The insulin signaling pathway regulates whole-body glucose homeostasis by transducing extracellular signals from the insulin receptor (IR) to downstream intracellular targets, thus coordinating a multitude of biological functions. Dysregulation of IR or its signal transduction is associated with insulin resistance, which may culminate in type 2 diabetes. Following initial stimulation of IR, insulin signaling diverges into different pathways, activating multiple substrates that have roles in various metabolic and cellular processes. The integration of multiple pathways arising from IR activation continues to expand as new IR substrates are identified and characterized. Accordingly, our review will focus on roles for IR substrates as they pertain to three primary areas: metabolism/glucose uptake, mitogenesis/growth, and aging/longevity. While IR functions in a seemingly pleiotropic manner in many cell types, through these three main roles in fat and skeletal muscle cells, IR multi-tasks to regulate whole-body glucose homeostasis to impact healthspan and lifespan. 相似文献
17.
Cell surface receptors are used to transmit extracellular information. The activation of cell surface receptors initiates signal transduction and receptor endocytosis. Signal transduction and the endosomal transport of activated receptors require precise regulation. New concepts for the integration of endocytosis and signaling arise from recent findings that suggest bidirectional interplay of these two processes. This review discusses the following questions: (i) do activated cell surface receptors modify the endosomal system to promote internalization and endosomal traffic, and (ii) do internalized cell surface receptors use specifically localized signaling complexes to generate specific biological signals? 相似文献
18.
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
19.
Ryan T. Kendall Louis M. Luttrell 《Cellular and molecular life sciences : CMLS》2009,66(18):2953-2973
The termination of heptahelical receptor signaling is a multilevel process coordinated, in large part, by members of the arrestin
family of proteins. Arrestin binding to agonist-occupied receptors promotes desensitization by interrupting receptor-G protein
coupling, while simultaneously recruiting machinery for receptor endocytosis, vesicular trafficking, and receptor fate determination.
By simultaneously binding other proteins, arrestins also act as ligand-regulated scaffolds that recruit protein and lipid
kinase, phosphatase, phosphodiesterase, and ubiquitin ligase activity into receptor-based multiprotein ‘signalsome’ complexes.
Arrestin-binding thus ‘switches’ receptors from a transient G protein-coupled state to a persistent arrestin-coupled state
that continues to signal as the receptor transits intracellular compartments. While it is clear that signalsome assembly has
profound effects on the duration and spatial characteristics of heptahelical receptor signals, the physiologic functions of
this novel signaling mechanism are poorly understood. Growing evidence suggests that signalsomes regulate such diverse processes
as endocytosis and exocytosis, cell migration, survival, and contractility. 相似文献