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1.
The polycystins: a novel class of membrane-associated proteins involved in renal cystic disease 总被引:2,自引:0,他引:2
Sandford R Mulroy S Foggensteiner L 《Cellular and molecular life sciences : CMLS》1999,56(7-8):567-579
Polycystin-1, polycystin-2 and polycystin-L are the predicted protein products of the PKD1, PKD2 and PKDL genes, respectively.
Mutations in PKD1 and PKD2 are responsible for almost all cases of autosomal dominant polycystic kidney disease (ADPKD). This
condition is one of the commonest mendelian disorders of man with a prevalence of 1:800 and is responsible for nearly 10%
of cases of end-stage renal failure in adults. The cloning of PKD1 and PKD2 in recent years has provided the initial steps
in defining the mechanisms underlying renal cyst formation in this condition, with the aim of defining pharmacological and
genetic interventions that may ameliorate the diverse and often serious clinical manifestations of this disease. The PKD genes
share regions of sequence similarity, and all predict integral membrane proteins. Whilst the predicted protein domain structure
of polycystin-1 suggests it is involved in cell-cell or cell-matrix interactions, the similarity of polycystin-2 and polycystin-L
to the pore-forming domains of some cation channels suggests that they all form subunits of a large plasma membrane ion channel.
In the few years since the cloning of the PKD genes, a consensus that defines the range of mutations, expression pattern,
interactions and functional domains of these genes and their protein products is emerging. This review will therefore attempt
to summarise these data and provide an insight in to the key areas in which polycystin research is unravelling the mechanisms
involved in renal cyst formation.
Received 22 February 1999; received after revision 5 July 1999; accepted 6 July 1999 相似文献
2.
Kirkpatrick DT 《Cellular and molecular life sciences : CMLS》1999,55(3):437-449
Numerous proteins are involved in the nucleotide excision repair (NER) and DNA mismatch repair (MMR) pathways. The function
and specificity of these proteins during the mitotic cell cycle has been actively investigated, in large part due to the involvement
of these systems in human diseases. In contrast, comparatively little is known about their functioning during meiosis. At
least three repair pathways operate during meiosis in the yeast Saccharomyces cerevisiae to repair mismatches that occur as a consequence of heteroduplex formation in recombination. The first pathway is similar
to the one acting during postreplicative mismatch repair in mitotically dividing cells, while two pathways are responsible
for the repair of large loops during meiosis, using proteins from MMR and NER systems. Some MMR proteins also help prevent
recombination between diverged sequences during meiosis, and act late in recombination to affect the resolution of crossovers.
This review will discuss the current status of DNA mismatch repair and nucleotide excision repair proteins during meiosis,
especially in the yeast S. cerevisiae.
Received 21 September 1998; received after revision 23 November 1998; accepted 23 November 1998 相似文献
3.
One of the central elements of excitation-contraction coupling, the voltage-sensing dihydropyridine receptor, is believed
to exist as a high-molecular-mass complex in the triad junction. Although freeze-fracture electron microscopical analysis
suggests a tetrad complex, no direct biochemical evidence exists demonstrating the actual size of the native membrane complex.
Using a combination of various two-dimensional gel electrophoresis techniques, we show here that the principal α
1-subunit of the dihydropyridine receptor and its auxiliary α
2-subunit form a triad complex of approximately 2800 kDa under native conditions. Established Ca2+-ATPase tetramers and calsequestrin monomers were employed for the internal standardization of the gel systems used. Thus,
the large voltage-sensing complex appears to be tightly associated, since it does not disintegrate during subcellular fractionation
and native electrophoresis procedures. Our findings support the cell biological hypothesis that native dihydropyridine receptor
units form a tetrad structure within the transverse tubules.
Received 10 October 2000; revised 28 November 2000; accepted 4 January 2001 相似文献
4.
Eukaryotic nitrate and nitrite transporters 总被引:12,自引:0,他引:12
Nitrate transport is the key step controlling the amount of nitrate incorporated by the cells and subsequent of storage,
reduction or export. Molecular, genetic and biochemical approaches to the study of eukaryotic nitrate/nitrite transporters
allow an initial understanding of this step, which is much more complex and structured than previously suspected. At the plasma
membrane level, two gene families, Nrt1 and Nrt2, account for high- and low-affinity nitrate transporters. Functionality of NRT1 from Arabidopsis and NRT2 proteins from Aspergillus and Chlamydomonas has been demonstrated. However, redundancy of these systems makes it difficult to assign particular physiological roles to
each. Data on genes involved in the regulation of nitrate transport and reduction are still scarce. Information on nitrite
transporters to the chloroplast is biased by the belief that in vivo nitrous acid diffuses freely to this organellum. The
recent progress on these aspects is discussed in this review. 相似文献
5.
Presenilin-2 (PS2) is one of three genes [amyloid precursor protein (APP), presenilin-1 (PS1) and PS2] shown to cause familial Alzheimer's disease (FAD), and is highly homologous to PS1. Currently demonstrated functions of PS2 include interactions with APP and Aβ, and participation in apoptotic pathways. PS2 FAD mutations influence APP processing in a manner predicted to promote amyloid formation and also enhance the proapoptotic effect of wild-type PS2. Other possible functions of PS2 are related to its homology to Notch pathway genes in Caenorhabditis elegans, suggesting it may have a developmental role. PS2-associated AD is the most reminiscent of the sporadic form of the disease in terms of older age of onset and longer disease
duration. Since PS2 mutations are incompletely penetrant and age of onset in carriers is highly variable (40 – 88 years), elucidation of PS2 mechanisms may reveal factors which modify AD and are therapeutically relevant to sporadic AD. 相似文献
6.
Prosperi-Meys C Wouters J Galleni M Lamotte-Brasseur J 《Cellular and molecular life sciences : CMLS》2001,58(14):2136-2143
Increased resistance to β-lactam antibiotics is mainly due to β-lactamases whose production by pathogenic bacteria makes their broad activity spectrum
especially frightening. X-ray structures of several zinc β-lactamases have revealed the coordination of the two metal ions, but their mode of action remains unclear. Geometry optimisation
of stable complexes along the reaction pathway of benzylpenicillin hydrolysis highlighted a proton shuttle occurring from
D120 of the Bacillus cereus β-lactamase to the β-lactam nitrogen via Zn2 which is central to the network. First, the Zn1 ion has a structural role maintaining Zn-bound waters,
WAT1 and WAT2, either directly or through the Zn1 tetrahedrally coordinated histidine ligands. The Zn2 ion has a more catalytic
role, stabilising the tetrahedral intermediate, accepting the β-lactam nitrogen atom as a ligand. The role of Zn2 and the flexibility in the coordination geometry of both Zn ions is of
crucial importance for catalysis.
Received 14 August 2001; received after revision 19 October 2001; accepted 30 October 2001 相似文献
7.
Protein kinase-dependent overexpression of the nuclear protein pirin in c-JUN and RAS transformed fibroblasts 总被引:1,自引:0,他引:1
Bergman AC Alaiya AA Wendler W Binetruy B Shoshan M Sakaguchi K Bergman T Kronenwett U Auer G Appella E Jörnvall H Linder S 《Cellular and molecular life sciences : CMLS》1999,55(3):467-471
Signalling via the protein kinase Raf-MEK-ERK pathway is of major importance for transformation by oncogenes. To identify
genes affected by inhibition of this pathway, c-JUN transformed rat fibroblasts were treated with a MEK1 inhibitor (PD98059) and subjected to two-dimensional gel electrophoresis
after cell lysis. Gene products with expression influenced by MEK1 inhibition were determined by mass spectrometry of fragments
from in-gel tryptic digestions. The expression of pirin, a nuclear factor I-interacting protein, was lowered after inhibition
of MEK1. Western blot analysis revealed increased expression of pirin in RAS and c-JUN transformed cells in the absence of PD98059. Inhibition of MEK1 also led to reduced expression of α-enolase, phosphoglycerate kinase, elongation factor 2 and heterogeneous nuclear ribonucleoprotein A3, the latter two being
detected as truncated proteins. In contrast, the level of ornithine aminotransferase was increased. We conclude that inhibition
of MEK1 results in major alterations of protein expression in c-JUN transformed cells, suggesting that this pathway is important for oncogene-induced phenotypic changes.
Received 30 December 1998; accepted 12 January 1999 相似文献
8.
An anti-Bcl-2 antibody prevents 2-deoxy-D-ribose-induced apoptosis in the IPLB-LdFB insect cell line
Barbieri D Malagoli D Cuoghi B Ottaviani E 《Cellular and molecular life sciences : CMLS》2001,58(4):653-659
Confocal microscopy reveals that the anti-Bcl-2 antibody (pAb) is able to diffuse across the plasma membrane of the fat body
cell line IPLB-LdFB from the insect Lymantria dispar, demonstrating the presence of Bcl-2-like molecules in the cytoplasm. Immunoperoxidase procedure confirms the cellular localization.
Furthermore, an immunoprecipitation corresponding to a molecular weight of 29 KDa is observed with western blot analysis using
the anti-Bcl-2 pAb. Cytofluorimetric experiments show that anti-Bcl-2 pAb counteracts 2-deoxy-d-ribose-induced apoptosis and provokes morphological changes in the insect cell line, i.e. a reduction in cell size, the disappearance
of the vacuola and changes in shape. At the same time, the antibody provokes mitochondrial membrane depolarization, and N-acetyl-l-cysteine is unable to reconstitute the physiological conditions. The present findings suggest that Bcl-2-like proteins play
a main role in maintaining of the integrity of cellular components, e.g. mitochondria, rather than in controlling programmed
cell death.
Received 23 January 2001; received after revision 1 March 2001; accepted 1 March 2001 相似文献
9.
Izaurralde E 《Cellular and molecular life sciences : CMLS》2001,58(8):1105-1112
The distinguishing feature of eukaryotic cells is the segregation of RNA biogenesis and DNA replication in the nucleus, separate
from the cytoplasmic machinery for protein synthesis. As a consequence, messenger RNAs (mRNAs) and all cytoplasmic RNAs from
nuclear origin need to be transported from their site of synthesis in the nucleus to their final cytoplasmic destination.
Nuclear export occurs through nuclear pore complexes (NPCs) and is mediated by saturable transport receptors, which shuttle
between the nucleus and cytoplasm. The past years have seen great progress in the characterization of the mRNA export pathway
and the identification of proteins involved in this process. A novel family of nuclear export receptors (the NXF family),
distinct from the well-characterized family of importin β-like proteins, has been implicated in the export of mRNA to the cytoplasm.
Received 23 January 2001; received after revision 12 April 2001; accepted 12 April 2001 相似文献
10.
Apaf1 has been described as the core of the apoptosome. Deficiency in murine Apaf1 leads to embryonic lethality with a phenotype affecting many aspects of developmental apoptosis. In the developing brain,
Apaf1 is a death regulator of the neuronal founder cells. Combined intercrosses of mouse lines mutant for members of the mitochondrial
death pathway are providing us with some clues about the relative regulation existing among neuronal cell populations. Apaf1-deficient embryos display an interesting phenotype in the inner ear and in limb development, which involves different caspase-dependent
and -independent pathways. Moreover, APAF1 is mutated in human melanomas, and its depletion contributes to malignant transformation in a mouse model of cancer. This
review has a double aim: the analysis of the alternatives taken by the embryo to bring into the suicidal program different
cells at different stages, and the relevance of APAF1 in the onset and progression of cancer.
Received 5 March 2001; received after revision 19 April 2001; accepted 4 May 2001 相似文献
11.
Protein farnesylation in mammalian cells: effects of farnesyltransferase inhibitors on cancer cells 总被引:3,自引:0,他引:3
F. Tamanoi C.-L. Gau C. Jiang H. Edamatsu J. Kato-Stankiewicz 《Cellular and molecular life sciences : CMLS》2001,58(11):1636-1649
Protein farnesylation, catalyzed by protein farnesyltransferase, plays important roles in the membrane association and protein-protein
interaction of a number of eukaryotic proteins. Recent development of farnesyltransferase inhibitors (FTIs) has led to further
insight into the biological significance of farnesylation in cancer cells. A number of reports point to the dramatic effects
FTIs exert on cancer cells. In addition to inhibiting anchorage-independent growth, FTIs cause changes in the cell cycle either
at the G1/S or at the G2/M phase. Furthermore, induction of apoptosis by FTIs has been reported. FTIs also affects the actin
cytoskeleton and cell morphology. This review summarizes these reports and discusses implications for farnesylated proteins
responsible for these FTI effects.
Received 17 April 2001; received after revision 28 May 2001; accepted 28 May 2001 相似文献
12.
Qingdi Quentin Li Iawen Hsu Thomas Sanford Reema Railkar Navin Balaji Carole Sourbier Cathy Vocke K. C. Balaji Piyush K. Agarwal 《Cellular and molecular life sciences : CMLS》2018,75(5):939-963
The protein kinase D (PKD) family of proteins are important regulators of tumor growth, development, and progression. CRT0066101, an inhibitor of PKD, has antitumor activity in multiple types of carcinomas. However, the effect and mechanism of CRT0066101 in bladder cancer are not understood. In the present study, we show that CRT0066101 suppressed the proliferation and migration of four bladder cancer cell lines in vitro. We also demonstrate that CRT0066101 blocked tumor growth in a mouse flank xenograft model of bladder cancer. To further assess the role of PKD in bladder carcinoma, we examined the three PKD isoforms and found that PKD2 was highly expressed in eight bladder cancer cell lines and in urothelial carcinoma tissues from the TCGA database, and that short hairpin RNA (shRNA)-mediated knockdown of PKD2 dramatically reduced bladder cancer growth and invasion in vitro and in vivo, suggesting that the effect of the compound in bladder cancer is mediated through inhibition of PKD2. This notion was corroborated by demonstrating that the levels of phospho-PKD2 were markedly decreased in CRT0066101-treated bladder tumor explants. Furthermore, our cell cycle analysis by flow cytometry revealed that CRT0066101 treatment or PKD2 silencing arrested bladder cancer cells at the G2/M phase, the arrest being accompanied by decreases in the levels of cyclin B1, CDK1 and phospho-CDK1 (Thr161) and increases in the levels of p27Kip1 and phospho-CDK1 (Thr14/Tyr15). Moreover, CRT0066101 downregulated the expression of Cdc25C, which dephosphorylates/activates CDK1, but enhanced the activity of the checkpoint kinase Chk1, which inhibits CDK1 by phosphorylating/inactivating Cdc25C. Finally, CRT0066101 was found to elevate the levels of Myt1, Wee1, phospho-Cdc25C (Ser216), Gadd45α, and 14-3-3 proteins, all of which reduce the CDK1-cyclin B1 complex activity. These novel findings suggest that CRT0066101 suppresses bladder cancer growth by inhibiting PKD2 through induction of G2/M cell cycle arrest, leading to the blockade of cell cycle progression. 相似文献
13.
MDA-MB-468 is a human mammary adenocarcinoma cell line that overexpresses the epidermal growth factor (EGF) receptor and
undergoes programmed cell death (apoptosis) in response to EGF treatment. Programmed cell death was shown to be greatly enhanced
when cells were growth-arrested prior to EGF treatment. Apoptosis was characterized by an initial rounding up and detachment
of the cells from their substrate starting about 12 h after EGF treatment, followed by chromatin condensation, nuclear fragmentation
and oligonucleosomal fragmentation of the DNA at about 24 to 48 h. Cell death was dependent on de novo protein synthesis.
We found a rapid induction of c-fos, c-jun and junB at the mRNA level after about 30 min of EGF treatment and a more delayed upregulation of fosB and fra-1. The junD gene was expressed in the absence of EGF, and it was moderately induced within 30 min of growth factor addition. The increase
of the different fos and jun mRNAs were paralleled by an increase of activator protein-1 (AP-1) DNA binding activity. A characterization of the AP-1 complex
revealed similar levels of several Fos and Jun proteins. Based on the kinetics of AP-1 accumulation and cell death, it seems
likely that AP-1 contributes to the apoptotic cell death of EGF receptor-overexpressing MDA-MB-468 cells.
Received 21 July 1997; received after revision 6 November 1997; accepted 6 November 1997 相似文献
14.
In human patients, blood coagulation disorders often associate with cancer, even in its early stages. Recently, in vitro and in vivo experimental models have shown that oncogene expression, or inactivation of tumour suppressor genes, upregulate genes that
control blood coagulation. These studies suggest that activation of blood clotting, leading to peritumoral fibrin deposition,
is instrumental in cancer development. Fibrin can indeed build up a provisional matrix, supporting the invasive growth of
neoplastic tissues and blood vessels. Interference with blood coagulation can thus be considered as part of a multifaceted
therapeutic approach to cancer.
Received 30 November 2005; received after revision 7 February 2005; accepted 8 February 2006 相似文献
15.
Salminen A Ojala J Huuskonen J Kauppinen A Suuronen T Kaarniranta K 《Cellular and molecular life sciences : CMLS》2008,65(7-8):1049-1058
Research on aging in model organisms has revealed different molecular mechanisms involved in the regulation of the lifespan.
Studies on Saccharomyces cerevisiae have highlighted the role of the Sir2 family of genes, human Sirtuin homologs, as the longevity factors. In Caenorhabditis elegans, the daf-16 gene, a mammalian homolog of FoxO genes, was shown to function as a longevity gene. A wide array of studies has
provided evidence for a role of the activation of innate immunity during aging process in mammals. This process has been called
inflamm-aging. The master regulator of innate immunity is the NF-κB system. In this review, we focus on the several interactions
of aging-associated signaling cascades regulated either by Sirtuins and FoxOs or NF-κB signaling pathways. We provide evidence
that signaling via the longevity factors of FoxOs and SIRT1 can inhibit NF-κB signaling and simultaneously protect against inflamm-aging process.
Received 4 October 2007; received after revision 7 November 2007; accepted 9 November 2007 相似文献
16.
Albert Lee Stephanie L. Rayner Serene S. L. Gwee Alana De Luca Hamideh Shahheydari Vinod Sundaramoorthy Audrey Ragagnin Marco Morsch Rowan Radford Jasmin Galper Sarah Freckleton Bingyang Shi Adam K. Walker Emily K. Don Nicholas J. Cole Shu Yang Kelly L. Williams Justin J. Yerbury Ian P. Blair Julie D. Atkin Mark P. Molloy Roger S. Chung 《Cellular and molecular life sciences : CMLS》2018,75(2):335-354
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase (SCFcyclin F) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin FS621G caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin FWT. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin FS621G-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin FS621G revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin FS621G disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis. 相似文献
17.
The mitochondrial PHB complex: roles in mitochondrial respiratory complex assembly, ageing and degenerative disease 总被引:16,自引:0,他引:16
Nijtmans LG Artal SM Grivell LA Coates PJ 《Cellular and molecular life sciences : CMLS》2002,59(1):143-155
Although originally identified as putative negative regulators of the cell cycle, recent studies have demonstrated that the
PHB proteins act as a chaperone in the assembly of subunits of mitochondrial respiratory chain complexes. The two PHB proteins,
Phb1p and Phb2p, are located in the mitochondrial inner membrane where they form a large complex that represents a novel type
of membrane-bound chaperone. On the basis of its native molecular weight, the PHB-complex should contain 12-14 copies of both
Phb1p and Phb2p. The PHB complex binds directly to newly synthesised mitochondrial translation products and stabilises them
against degradation by membrane-bound metalloproteases belonging to the family of mitochondrial triple-A proteins. Sequence
homology assigns Phb1p and Phb2p to a family of proteins which also contains stomatins, HflKC, flotillins and plant defence
proteins. However, to date only the bacterial HflKC proteins have been shown to possess a direct functional homology with
the PHB complex. Previously assigned actions of the PHB proteins, including roles in tumour suppression, cell cycle regulation,
immunoglobulin M receptor binding and apoptosis seem unlikely in view of any hard evidence in their support. Nevertheless,
because the proteins are probably indirectly involved in ageing and cancer, we assess their possible role in these processes.
Finally, we suggest that the original name for these proteins, the prohibitins, should be amended to reflect their roles as
proteins that hold badly formed subunits, thereby keeping the nomenclature already in use but altering its meaning to reflect
their true function more accurately.
Received 21 May 2001; received after revision 2 July 2001; accepted 24 July 2001 相似文献
18.
The BAG (Bcl-2 associated athanogene) family is a multifunctional group of proteins that perform diverse functions ranging from apoptosis to tumorigenesis.
An evolutionarily conserved group, these proteins are distinguished by a common conserved region known as the BAG domain.
BAG genes have been found in yeasts, plants, and animals, and are believed to function as adapter proteins forming complexes
with signaling molecules and molecular chaperones. In humans, a role for BAG proteins has been suggested in carcinogenesis,
HIV infection, and Parkinson’s disease. These proteins are therefore potential therapeutic targets, and their expression in
cells may serve as a predictive tool for such diseases. In plants, the Arabidopsis thaliana genome contains seven homologs of the BAG family, including four with domain organization similar to animal BAGs. Three members
contain a calmodulin-binding domain possibly reflecting differences between plant and animal programmed cell death. This review
summarizes current understanding of BAG proteins in both animals and plants.
Received 21 November 2007; received after revision 17 December 2007; accepted 2 January 2008 相似文献
19.
Evidence of undiscovered cell regulatory mechanisms: phosphoproteins and protein kinases in mitochondria 总被引:3,自引:0,他引:3
Thomson M 《Cellular and molecular life sciences : CMLS》2002,59(2):213-219
The finding that mitochondria contain substrates for protein kinases lead to the discovery that protein kinases are located
in the mitochondria of certain tissues and species. These include pyruvate dyhydrogenase kinase, branched-chain α-ketoacid dehydrogenase kinase, protein kinase A, protein kinase Cδ, stress-activated kinase and A-Raf as well as unidentified kinases. Recent evidence suggests that mitochondrial protein kinases
may be involved in physiological processes such as apoptosis and steroidogenesis. Additionally, the novel finding of low-molecular-weight
GTP-binding proteins in mitochondria suggests the possibility that these may interact with mitochondrial protein kinases to
regulate the activity of mitochondrial effector proteins. The fact that there are components of cellular regulatory systems
in mitochondria indicates the exciting possibility of undiscovered systems regulating mitochondrial physiology.
Received 19 June 2001; received after revision 7 August 2001; accepted 8 August 2001 相似文献
20.
Edouard T Montagner A Dance M Conte F Yart A Parfait B Tauber M Salles JP Raynal P 《Cellular and molecular life sciences : CMLS》2007,64(13):1585-1590
Activating and inactivating mutations of SHP-2 are responsible, respectively, for the Noonan (NS) and the LEOPARD (LS) syndromes.
Clinically, these developmental disorders overlap greatly, resulting in the apparent paradox of similar diseases caused by
mutations that oppositely influence SHP-2 phosphatase activity. While the mechanisms remain unclear, recent functional analysis
of SHP-2, along with the identification of other genes involved in NS and in other related syndromes (neurofibromatosis-1,
Costello and cardio-facio-cutaneous syndromes), strongly suggest that Ras/MAPK represents the major signaling pathway deregulated
by SHP-2 mutants. We discuss the idea that, with the exception of LS mutations that have been shown to exert a dominant negative
effect, all disease-causing mutations involved in Ras/MAPK-mediated signaling, including SHP-2, might lead to enhanced MAPK
activation. This suggests that a narrow range of MAPK signaling is required for appropriate development. We also discuss the
possibility that LS mutations may not simply exhibit dominant negative activity.
Received 30 November 2006; received after revision 8 February 2007; accepted 13 March 2007 相似文献