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1.
Cerebral cavernous malformations (CCM) are neurovascular dysplasias that result in mulberry-shaped lesions predominantly located in brain and spinal tissues. Mutations in three genes are associated with CCM. These genes encode for the proteins KRIT1/CCM1 (krev interaction trapped 1/cerebral cavernous malformations 1), cerebral cavernous malformations 2, osmosensing scaffold for MEKK3 (CCM2/malcavernin/OSM), and cerebral cavernous malformations 3/programmed cell death 10 (CCM3/PDCD10). There have been many significant recent advances in our understanding of the structure and function of these proteins, as well as in their roles in cellular signaling. Here, we provide an update on the current knowledge of the structure of the CCM proteins and their functions within cellular signaling, particularly in cellular adhesion complexes and signaling cascades. We go on to discuss subcellular localization of the CCM proteins, the formation and regulation of the CCM complex signaling platform, and current progress towards targeted therapy for CCM disease. Recent structural studies have begun to shed new light on CCM protein function, and we focus here on how these studies have helped inform the current understanding of these roles and how they may aid future studies into both CCM-related biology and disease mechanisms. 相似文献
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Trimeric guanine nucleotide-binding proteins (G proteins) function as the key regulatory elements in a number of transmembrane
signaling cascades where they convey information from agonist-activated receptors to effector molecules. The subcellular localization
of G proteins is directly related to their functional role, i.e., the dominant portion of the cellular pool of G proteins
resides in the plasma membrane. An intimate association of G protein subunits with the plasma membrane has been well known
for a long time. However, results of a number of independent studies published in the past decade have indicated clearly that
exposure of intact target cells to agonists results in subcellular redistribution of the cognate G proteins from plasma membranes
to the light-vesicular membrane fractions, in internalization from the cell surface into the cell interior and in transfer
from the membrane to the soluble cell fraction (high-speed supernatant), i.e., solubilization. Solubilization of G protein
α subunits as a consequence of stimulation of G protein-coupled receptors (GPCRs) with agonists has also been observed in
isolated membrane preparations. The membrane-cytosol shift of G proteins was detected even after direct activation of these
proteins by non-hydrolyzable analogues of GTP or by cholera toxin-induced ADP-ribosylation. In addition, prolonged stimulation
of GPCRs with agonists has been shown to lead to down-regulation of the relevant G proteins. Together, these data suggest
that G proteins might potentially participate in a highly complex set of events, which are generally termed desensitization
of the hormone response. Internalization, subcellular redistribution, solubilization, and down-regulation of trimeric G proteins
may thus provide an additional means (i.e., beside receptor-based mechanisms) to dampen the hormone or neurotransmitter response
after sustained (long-term) exposure.
Received 31 August 2001; received after revision 31 October 2001; accepted 7 November 2001 相似文献
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Mammalian target of rapamycin (mTOR) is a protein serine/threonine kinase that controls a wide range of growth-related cellular
processes. In the past several years, many factors have been identified that are involved in controlling mTOR activity. Those
factors in turn are regulated by diverse signaling cascades responsive to changes in intracellular and environmental conditions.
The molecular connections between mTOR and its regulators form a complex signaling network that governs cellular metabolism,
growth and proliferation. In this review, we discuss some key factors in mTOR regulation and mechanisms by which these factors
control mTOR activity. 相似文献
4.
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
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Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels belong to the superfamily of voltage-gated pore loop channels. HCN channels are unique among
vertebrate voltage-gated ion channels, in that they have a reverse voltage-dependence that leads to activation upon hyperpolarization.
In addition, voltage-dependent opening of these channels is directly regulated by the binding of cAMP. HCN channels are encoded
by four genes (HCN1–4) and are widely expressed throughout the heart and the central nervous system. The current flowing through
HCN channels, designated Ih or If, plays a key role in the control of cardiac and neuronal rhythmicity (“pacemaker current”). In addition, Ih contributes to several other neuronal processes, including determination of resting membrane potential, dendritic integration
and synaptic transmission. In this review we give an overview on structure, function and regulation of HCN channels. Particular
emphasis will be laid on the complex roles of these channels for neuronal function and cardiac rhythmicity.
Received 22 August 2008; received after revision 22 September 2008; accepted 24 September 2008 相似文献
8.
Protein tyrosine phosphatases (PTPs) have emerged as a new class of signaling molecules that play important roles in the development and function of the central nervous system. They include both tyrosine-specific and dual-specific phosphatases. Based on their cellular localization they are also classified as receptor-like or intracellular PTP. However, the intracellular mechanisms by which these PTPs regulate cellular signaling pathways are not well understood. Evidence gathered to date provides some insight into the physiological function of these PTPs in the nervous system. In this review, we outline what is currently known about the functional role of PTPs expressed in the brain.Received 31 March 2003; received after revision 7 May 2003; accepted 22 May 2003 相似文献
9.
Transmembrane ion channels play a crucial role in the existence of all living organisms. They partition the exterior from
the interior of the cell, maintain the proper ionic gradient across the cell membrane and facilitate signaling between cells.
To perform these functions, ion channels must be highly selective, allowing some types of ions to pass while blocking the
passage of others. Here we review a number of studies that have helped to elucidate the mechanisms by which ion channels discriminate
between ions of differing charge, focusing on four channel families as examples: gramicidin, ClC chloride, voltage-gated calcium
and potassium channels. The recent availability of high-resolution structural data has meant that the specific inter-atomic
interactions responsible for valence selectivity can be pinpointed. Not surprisingly, electrostatic considerations have been
shown to play an important role in ion specificity, although many details of the origins of this discrimination remain to
be determined.
Received 4 September 2005; received after revision 17 October 2005; accepted 2 November 2005 相似文献
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Trefoil factors 总被引:4,自引:0,他引:4
12.
Nakamura T Mito T Bando T Ohuchi H Noji S 《Cellular and molecular life sciences : CMLS》2008,65(1):64-72
Nymphs of hemimetabolous insects such as cockroaches and crickets exhibit a remarkable capacity for regenerating complex structures from damaged legs. Until recent years, however, approaches to elucidate the molecular mechanisms underlying the leg regeneration process have been lacking. Taking the cricket Gryllus bimaculatus as a model, we found that a phenotype related to regeneration frequently appears during leg regeneration, even though no phenotype is induced by RNA interference (RNAi) in the cricket nymph, designated as regeneration-dependent RNAi. Since then, we have investigated the functions of various genes encoding signaling factors and cellular adhesion proteins like Fat and Dachsous during leg regeneration. In this review, we summarize the classical knowledge about insect leg regeneration and introduce recent advances concerning the signaling cascades required for regenerating a leg. Our results provide clues to the mechanisms of regeneration which are relevant to vertebrate systems. 相似文献
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Signaling pathways between the plasma membrane and endoplasmic reticulum calcium stores 总被引:6,自引:0,他引:6
This review discusses multiple ways in which the endoplasmic reticulum participates in and is influenced by signal transduction pathways. The endoplasmic reticulum provides a Ca2+ store that can be mobilized either by calcium-induced calcium release or by the diffusible messenger inositol 1,4,5-trisphosphate. Depletion of endoplasmic reticulum Ca2+ stores provides a signal that activates surface membrane Ca2+ channels, a process known as capacitative calcium entry. Depletion of endoplasmic reticulum stores can also signal long-term cellular responses such as gene expression and programmed cell death or apoptosis. In addition to serving as a source of cellular signals, the endoplasmic reticulum is also functionally and structurally modified by the Ca2+ and protein kinase C pathways. Elevated cytoplasmic Ca2+ causes a rearrangement and fragmentation of endoplasmic reticulum membranes. Protein kinase C activation reduces the storage capacity of the endoplasmic reticulum Ca2+ pool. In some cell types, protein kinase C inhibits capacitative calcium entry. Protein kinase C activation also protects the endoplasmic reticulum from the structural effects of high cytoplasmic Ca2+. The emerging view is one of a complex network of pathways through which the endoplasmic reticulum and the Ca2+ and protein kinase C signaling pathways interact at various levels regulating cellular structure and function. 相似文献
15.
Reelin-Disabled-1 (Dab1) signaling has a well-established role in regulating neuronal migration during brain development. Binding of Reelin to its receptors induces Dab1 tyrosine phosphorylation. Tyrosine-phosphorylated Dab1 recruits a wide range of SH2 domain-containing proteins and activates multiple signaling cascades, resulting in cytoskeleton remodeling and precise neuronal positioning. In this review, we summarize recent progress in the Reelin-Dab1 signaling field. We focus on Dab1 alternative splicing as a mechanism for modulating the Reelin signal in developing brain. We suggest that correct positioning of neurons in the developing brain is at least partly controlled by alternatively-spliced Dab1 isoforms that differ in the number and type of tyrosine phosphorylation motifs that they contain. We propose a model whereby different subsets of SH2 domain-containing proteins are activated by different Dab1 isoforms, resulting in coordinated migration of neurons. 相似文献
16.
Sayuri Suzuki Annette Lis Carsten Schmitz Reinhold Penner Andrea Fleig 《Cellular and molecular life sciences : CMLS》2018,75(16):3069-3078
The melastatin-related transient receptor potential member 7 (TRPM7) is a unique fusion protein with both ion channel function and enzymatic α-kinase activity. TRPM7 is essential for cellular systemic magnesium homeostasis and early embryogenesis; it promotes calcium transport during global brain ischemia and emerges as a key player in cancer growth. TRPM7 channels are negatively regulated through G-protein-coupled receptor-stimulation, either by reducing cellular cyclic adenosine monophosphate (cAMP) or depleting phosphatidylinositol bisphosphate (PIP2) levels in the plasma membrane. We here identify that heterologous overexpression of human TRPM7-K1648R mutant will lead to disruption of protease or purinergic receptor-induced calcium release. The disruption occurs at the level of Gq, which requires intact TRPM7 kinase phosphorylation activity for orderly downstream signal transduction to activate phospholipase (PLC)β and cause calcium release. We propose that this mechanism may support limiting GPCR-mediated calcium signaling in times of insufficient cellular ATP supply. 相似文献
17.
D. Mekahli Jan B. Parys G. Bultynck L. Missiaen H. De Smedt 《Cellular and molecular life sciences : CMLS》2013,70(15):2697-2712
The cystic phenotype in autosomal dominant polycystic kidney disease is characterized by a profound dysfunction of many cellular signaling patterns, ultimately leading to an increase in both cell proliferation and apoptotic cell death. Disturbance of normal cellular Ca2+ signaling seems to be a primary event and is clearly involved in many pathways that may lead to both types of cellular responses. In this review, we summarize the current knowledge about the molecular and functional interactions between polycystins and multiple components of the cellular Ca2+-signaling machinery. In addition, we discuss the relevant downstream responses of the changed Ca2+ signaling that ultimately lead to increased proliferation and increased apoptosis as observed in many cystic cell types. 相似文献
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Regulatory mechanisms of mitogen-activated kinase signaling 总被引:5,自引:1,他引:4
MAP kinases (MAPKs) are evolutionarily conserved regulators that mediate signal transduction and play essential roles in various
physiological processes. There are three main families of MAPKs in mammals, whose functions are regulated by activators, inactivators,
substrates and scaffolds, which together form delicate signaling cascades in response to different extracellular or intracellular
stimulation. MAPK signaling is tightly regulated so that optimal biological activities are achieved and health is maintained.
However, how the specificity of the signaling flow along each cascade is achieved is still relatively unclear. In this review,
we summarize recent advances in understanding the regulation of MAPK cascades and the roles of MAP kinases and their regulators
in development and in immune responses.
Received 11 January 2007; received after revision 31 May 2007; accepted 5 July 2007 相似文献