Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breakdown of the pollination barrier of self-incompatibility (SI) in older flowers, a phenomenon known as pseudo-self-compatibility or transient SI, has been described as an advantageous reproductive assurance strategy that allows selfing after opportunities for out-crossing have been exhausted [1-9]. Pseudo-self-compatibility is quite prevalent as a mixed mating strategy in nature, but the underlying molecular mechanisms are not known. We had previously shown that Arabidopsis thaliana exhibits cryptic natural variation for pseudo-self-compatibility, which is uncovered by transformation of different accessions with SI specificity-determining SRK and SCR genes from its self-incompatible sister species A. lyrata[10, 11]. Here, by using this transgenic A. thaliana model, we show that pseudo-self-compatibility is caused by a hypomorphic allele of PUB8, an S-locus-linked gene encoding a previously uncharacterized ARM repeat- and U box-containing protein that regulates SRK transcript levels. This is the first gene underlying pseudo-self-compatibility to be identified and the first report in which cryptic natural variation unveiled by a transgene enabled the cloning of a gene for a complex trait.
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PMID:A cryptic modifier causing transient self-incompatibility in Arabidopsis thaliana. 1741 90

Self-incompatibility (SI) in the Brassicaceae plant family is controlled by the SRK and SCR genes situated at the S locus. A large number of S haplotypes have been identified, mainly in cultivated species of the Brassica and Raphanus genera, but recently also in wild Arabidopsis species. Here, we used DNA sequences from the SRK and SCR genes of the wild Brassica species Brassica cretica, together with publicly available sequence data from other Brassicaceae species, to investigate the evolutionary relationships among S haplotypes in the Brassicaceae family. The results reveal that wild and cultivated Brassica species have similar levels of SRK diversity, indicating that domestication has had but a minor effect on S-locus diversity in Brassica. Our results also show that a common set of S haplotypes was present in the ancestor of the Brassica and Arabidopsis genera, that only a small number of haplotypes survived in the Brassica lineage after its separation from Arabidopsis, and that diversification within the two Brassica dominance classes occurred after the split between the two lineages. We also found indications that recombination may have occurred between the kinase domain of SRK and the SCR gene in Brassica.
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PMID:The evolution and diversification of S-locus haplotypes in the Brassicaceae family. 1908 66

Self-incompatibility (SI) in plants is a classic example of a trait evolving under strong frequency-dependent selection. As a consequence, population genetic theory predicts that the S locus, which controls SI, should maintain numerous alleles, display a high level of nucleotide diversity, and, in structured populations, show a lower level of among-population differentiation compared to neutral loci. Population-level investigations of DNA sequence variation at the S locus have recently been carried out in the genus Arabidopsis, largely confirming results from theoretical models of S-locus evolutionary dynamics, but no comparable studies have been done in wild Brassica species. In this study, we sequenced parts of the S-locus genes SRK and SCR, two tightly linked genes that are directly involved in the determination of SI specificity in samples from four natural populations of the wild species Brassica cretica. The amount and distribution of nucleotide diversity, as well as the frequency spectrum of putative functional haplotypes, observed at the S locus in B. cretica fit very well with expectations from theoretical models, providing strong evidence for frequency-dependent selection acting on the S locus in a wild Brassica species.
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PMID:Molecular population genetics of the SRK and SCR self-incompatibility genes in the wild plant species Brassica cretica (Brassicaceae). 1908 67

Abnormalities in calcium handling have been implicated as a significant source of electrical instability in heart failure (HF). While these abnormalities have been investigated extensively in isolated myocytes, how they manifest at the tissue level and trigger arrhythmias is not clear. We hypothesize that in HF, triggered activity (TA) is due to spontaneous calcium release from the sarcoplasmic reticulum that occurs in an aggregate of myocardial cells (an SRC) and that peak SCR amplitude is what determines whether TA will occur. Calcium and voltage optical mapping was performed in ventricular wedge preparations from canines with and without tachycardia-induced HF. In HF, steady-state calcium transients have reduced amplitude [135 vs. 170 ratiometric units (RU), P < 0.05] and increased duration (252 vs. 229 s, P < 0.05) compared with those of normal. Under control conditions and during beta-adrenergic stimulation, TA was more frequent in HF (53% and 93%, respectively) compared with normal (0% and 55%, respectively, P < 0.025). The mechanism of arrhythmias was SCRs, leading to delayed afterdepolarization-mediated triggered beats. Interestingly, the rate of SCR rise was greater for events that triggered a beat (0.41 RU/ms) compared with those that did not (0.18 RU/ms, P < 0.001). In contrast, there was no difference in SCR amplitude between the two groups. In conclusion, TA in HF tissue is associated with abnormal calcium regulation and mediated by the spontaneous release of calcium from the sarcoplasmic reticulum in aggregates of myocardial cells (i.e., an SCR), but importantly, it is the rate of SCR rise rather than amplitude that was associated with TA.
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PMID:Spontaneous calcium release in tissue from the failing canine heart. 1966 36

Ever since Darwin's pioneering research, the evolution of self-fertilisation (selfing) has been regarded as one of the most prevalent evolutionary transitions in flowering plants. A major mechanism to prevent selfing is the self-incompatibility (SI) recognition system, which consists of male and female specificity genes at the S-locus and SI modifier genes. Under conditions that favour selfing, mutations disabling the male recognition component are predicted to enjoy a relative advantage over those disabling the female component, because male mutations would increase through both pollen and seeds whereas female mutations would increase only through seeds. Despite many studies on the genetic basis of loss of SI in the predominantly selfing plant Arabidopsis thaliana, it remains unknown whether selfing arose through mutations in the female specificity gene (S-receptor kinase, SRK), male specificity gene (S-locus cysteine-rich protein, SCR; also known as S-locus protein 11, SP11) or modifier genes, and whether any of them rose to high frequency across large geographic regions. Here we report that a disruptive 213-base-pair (bp) inversion in the SCR gene (or its derivative haplotypes with deletions encompassing the entire SCR-A and a large portion of SRK-A) is found in 95% of European accessions, which contrasts with the genome-wide pattern of polymorphism in European A. thaliana. Importantly, interspecific crossings using Arabidopsis halleri as a pollen donor reveal that some A. thaliana accessions, including Wei-1, retain the female SI reaction, suggesting that all female components including SRK are still functional. Moreover, when the 213-bp inversion in SCR was inverted and expressed in transgenic Wei-1 plants, the functional SCR restored the SI reaction. The inversion within SCR is the first mutation disrupting SI shown to be nearly fixed in geographically wide samples, and its prevalence is consistent with theoretical predictions regarding the evolutionary advantage of mutations in male components.
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PMID:Evolution of self-compatibility in Arabidopsis by a mutation in the male specificity gene. 2040 Sep 45

Self-incompatibility (SI) in Brassicaceae is sporophytically controlled by a single S-locus with multi allelic variety. The male S determinant, SP11/SCR (S-locus protein 11/S-locus cysteine-rich protein), is a small cysteine-rich protein, and the female S determinant, SRK (S-locus receptor kinase), functions as a receptor for SP11 at the surface of stigma papilla cells. Although a few of the following downstream factors in the SP11-SRK signaling cascade have been identified, a comprehensive understanding of the SI mechanism still remains unexplained in Brassicaceae. Analysis of self-compatible (SC) mutants is significant for understanding the molecular mechanism in SI reactions, thus we screened SC lines from a variety of Japanese bulk-populations of B. rapa vegetables. Two lines, TSC4 and TSC28, seem to have disruptions in the SI signaling cascade, while the other line, TSC2, seems to have a deficiency in a female S determinant, SRK. In TSC4 and TSC28, known SI-related factors, i.e. SRK, SP11, MLPK (M-locus protein kinase), THL (thioredoxin-h-like), and ARC1 (arm repeat containing 1), were expressed normally, and their expression levels were comparable with those in SI lines. On a B. rapa genetic linkage map, potential SC genes in TSC4 and TSC28 were mapped on linkage groups A3 and A1, respectively, whereas MLPK, ARC1, and THL were mapped on A3, A4, and A6, respectively. Although potential SC genes of TSC4 and MLPK were on the same linkage group, their positions were apparently independent. These results indicate that the SC genes of TSC4 and TSC28 are independent from the S-locus or known SI-related genes. Thus, the SC lines selected here have mutations in novel factors of the SI signaling cascade, and they will contribute to fill pieces in a signal transduction pathway of the SI system in Brassicaceae.
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PMID:Novel self-compatible lines of Brassica rapa L. isolated from the Japanese bulk-populations. 2055 95

Brassica napus, an allopolyploid species having the A genome of B. rapa and the C genome of B. oleracea, is self-compatible, although both B. rapa and B. oleracea are self-incompatible. We have previously reported that SP11/SCR alleles are not expressed in anthers, while SRK alleles are functional in the stigma in B. napus cv. 'Westar', which has BnS-1 similar to B. rapa S-47 and BnS-6 similar to B. oleracea S-15. This genotype is the most frequent S genotype in B. napus, and we hypothesized that the loss of the function of SP11 is the primary cause of the self-compatibility of 'Westar'. To verify this hypothesis, we transformed 'Westar' plants with the SP11 allele of B. rapa S-47. All the transgenic plants and their progeny were completely self-incompatible, demonstrating self-compatibility to be due to the S haplotype having the non-functional SP11 allele in the A genome, which suppresses a functional recessive SP11 allele in the C genome. An artificially synthesized B. napus line having two recessive SP11 alleles was developed by interspecific hybridization between B. rapa and B. oleracea. This line was self-incompatible, but F(1) hybrids between this line and 'Westar' were self-compatible. These results suggest that the self-compatibility mechanism of 'Westar' is applicable to F(1) seed production in B. napus.
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PMID:The self-compatibility mechanism in Brassica napus L. is applicable to F1 hybrid breeding. 2154 75

Since in most tumors multiple signaling pathways are involved, many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases. The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL, SCR, platelet derived growth factor, vascular endothelial growth factor receptor and epidermal growth factor receptor families. Both multi-kinase inhibitors and single-kinase inhibitors have advantages and disadvantages, which are related to potential resistance mechanisms, pharmacokinetics, selectivity and tumor environment. In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist. Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor. Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity, while differences in gene expression exist between tumor and stromal cells. Considering these aspects, one type of inhibitor can generally not be preferred above the other, but will depend on the specific genetic constitution of the patient and the tumor, allowing personalized therapy. The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered (epi)genetics of the tumor. This strategy might result in treatment by a single multi kinase inhibitor for one patient, but in treatment by a couple of single kinase inhibitors for other patients.
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PMID:Tyrosine kinase inhibitors: Multi-targeted or single-targeted? 2160 17

Mate selection and maintenance of genetic diversity is crucial to successful reproduction and species survival. Plants utilize self-incompatibility system as a genetic barrier to prevent self pollen from developing on the pistil, leading to hybrid vigor and diversity. In Brassica (canola, kale, and broccoli), an allele-specific interaction between the pollen SCR/SP11 (S-locus cysteine rich protein/S locus protein 11) and the pistil S Receptor Kinase, results in the activation of SRK which recruits the Arm Repeat Containing 1 (ARC1) E3 ligase to the proteasome. The targets of Arm Repeat Containing 1 are proposed to be compatibility factors, which when targeted for degradation by Arm Repeat Containing 1 results in pollen rejection. Despite the fact that protein degradation is predicted to be important for successful self-pollen rejection, the identity of the various proteins whose abundance is altered by the SI pathway has remained unknown. To identify potential candidate proteins regulated by the SI response, we have used the two-dimensional difference gel electrophoresis analysis, coupled with matrix-assisted laser desorption ionization/time of flight/MS. We identified 56 differential protein spots with 19 unique candidate proteins whose abundance is down-regulated following self-incompatible pollinations. The identified differentials are predicted to function in various pathways including biosynthetic pathways, signaling, cytoskeletal organization, and exocytosis. From the 19 unique proteins identified, we investigated the role of tubulin and the microtubule network during both self-incompatible and compatible pollen responses. Moderate changes in the microtubule network were observed with self-incompatible pollinations; however, a more distinct localized break-down of the microtubule network was observed during compatible pollinations, that is likely mediated by EXO70A1, leading to successful pollination.
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PMID:Proteomic analysis of Brassica stigmatic proteins following the self-incompatibility reaction reveals a role for microtubule dynamics during pollen responses. 2189 Apr 72

GH and prolactin (PRL) are structurally related hormones that exert important effects in disparate target tissues. Their receptors (GHR and PRLR) reside in the cytokine receptor superfamily and share signaling pathways. In humans, GH binds both GHR and PRLR, whereas PRL binds only PRLR. Both hormones and their receptors may be relevant in certain human and rodent cancers, including breast cancer. GH and PRL promote signaling in human T47D breast cancer cells that express both GHR and PRLR. Furthermore, GHR and PRLR associate in a fashion augmented acutely by GH, even though GH primarily activates PRLR, rather than GHR, in these cells. To better understand PRLR's impact, we examined the effects of PRLR knockdown on GHR availability and GH sensitivity in T47D cells. T47D-ShPRLR cells, in which PRLR expression was reduced by stable short hairpin RNA (shRNA) expression, were compared with T47D-SCR control cells. PRLR knockdown decreased the rate of GHR proteolytic turnover, yielding GHR protein increase and ensuing sensitization of these cells to GHR signaling events including phosphorylation of GHR, Janus kinase 2, and signal transducer and activator of transcription 5 (STAT5). Unlike in T47D-SCR cells, acute GH signaling in T47D-ShPRLR cells was not blocked by the PRLR antagonist G129R but was inhibited by the GHR-specific antagonist, anti-GHR(ext-mAb). Thus, GH's use of GHR rather than PRLR was manifested when PRLR was reduced. In contrast to acute effects, GH incubation for 2 h or longer yielded diminished STAT5 phosphorylation in T47D-ShPRLR cells compared with T47D-SCR, a finding perhaps explained by markedly greater GH-induced GHR down-regulation in cells with diminished PRLR. However, when stimulated with repeated 1-h pulses of GH separated by 3-h washout periods to more faithfully mimic physiological GH pulsatility, T47D-ShPRLR cells exhibited greater transactivation of a STAT5-responsive luciferase reporter than did T47D-SCR cells. Our data suggest that PRLR's presence meaningfully affects GHR use in breast cancer cells.
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PMID:The role of prolactin receptor in GH signaling in breast cancer cells. 2319 81


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