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PubMed2004

Clinicoprognostic significance of pRb1 pathway alterations in uterine endometrial adenocarcinoma.

Components of the pRb1 pathway play a pivotal role in regulating the G1/S transition in the cell cycle. This study investigated the association between pRb1-cyclin D1-cdk4-p16INK4A pathway alterations and the clinical and prognostic utility for women affected by primary uterine endometrial adenocarcinoma (EC). The study population consisted of 50 cases of EC patients who were investigated for RB1 and CDKN2A (alias p16INK4A) gene alterations, as well as for the expression pattern of pathway proteins. Altogether, pRb1 pathway alterations were noted in 54% (27 of 50) of ECs, and more frequently in advanced-stage uterine carcinomas (P=0.024, Fisher exact test). Loss of heterozygosity abnormalities in RB1 and CKDN2A coexisted with altered cyclin D1-cdk4 complex immunoreactivity only in 2 patients, both less than 50 years of age. With respect to pRb1 pathway alterations, however, the recurrence rate was not significantly different (P=0.477; log-rank test). Our results suggest that the progression of uterine endometrial adenocarcinoma is generally accompanied by increased frequency of pRb1 pathway alterations. Alterations of the retinoblastoma pathway may not be necessarily associated with the recurrence of EC.

Adenocarcinoma↗
PubMed2006

Variation in cisplatinum sensitivity is not associated with Fanconi Anemia/BRCA pathway inactivation in head and neck squamous cell carcinoma cell lines.

Fanconi Anemia has recently been associated with a high risk of head and neck squamous cell carcinoma (HNSCC). Inactivation of the Fanconi Anemia (FANC-BRCA) pathway via promoter methylation of the FANCF gene has been proposed to be responsible for variation in cisplatinum (CDDP) sensitivity seen in ovarian and HNSCCs. Promoter methylation of the FANCF gene has been observed in 15% of HNSCC specimens, but the relationship to FANC pathway activation and CDDP sensitivity has not been reported. In the present study, 10 HNSCC cell lines were examined for expression of nine genes involved in the FANC-BRCA pathway by RT-PCR: FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, BRCA1 and BRCA2. FANC pathway function was evaluated by western blotting for FANCD2 mono-ubiquitination. All of the cell lines were also analyzed for variation in CDDP cytotoxicity. While significant differences were found in CDDP cytotoxicity, Fanconi pathway defects are an infrequent cause, as no evidence of transcriptional down-regulation of FANCF or other FANC mRNAs, or functional FANC-BRCA pathway defects were observed. These findings suggest that the variation in CDDP sensitivity of many HNSCCs is most frequently due to factors other than FANC-BRCA pathway inactivation.

Adult↗
PubMed2005

The 1,4,5-inositol trisphosphate pathway is a key component in Fas-mediated hypertrophy in neonatal rat ventricular myocytes.

OBJECTIVE: Cardiac hypertrophy is a compensatory response to increased mechanical load. Since Fas receptor activation is an important component in hypertrophy induced by pressure- and volume-overload, deciphering the underlying signaling pathways is of prime importance. Based on our previous work showing that in mice and rats ventricular myocytes the electrophysiological disturbances and diastolic [Ca2+]i-rise caused by 3 h of Fas activation are dependent on the Fas-->phospholipase C (PLC)-->1,4,5-inositol trisphosphate (1,4,5-IP3)-->sarcoplasmic reticulum (SR) [Ca2+]i release pathway, we tested the hypothesis that this pathway is also critical for Fas-mediated hypertrophy. METHODS: The effects of 24 h Fas activation in cultured neonatal rat ventricular myocytes (NRVM) were analyzed by means of RT-PCR, Western blot, immunofluorescence and fura-2 fluorescence. RESULTS: Fas activation increased nuclei surface area, atrial natriuretic peptide and connexin43 (Cx43) mRNA, the protein levels of total Cx43 and non-phosphorylated Cx43, and sarcomeric actin, all indicating hypertrophy. Concomitantly, Fas activation decreased mRNA of SERCA2a, the ryanodine receptor (RyR) and nuclear IP3R3. Further, Fas activation caused NFAT nuclear translocation. The hypertrophy was abolished by U73122, xestospongin C (blockers of the 1,4,5-IP3 pathway), genistein and by the PI3K blocker LY294002. CONCLUSIONS: Fas-mediated hypertrophy is dependent on the 1,4,5-IP3 pathway, which is functionally inter-connected to the PI3K/AKT/GSK3beta pathway. Both pathways act in concert to cause NFAT nuclear translocation and subsequent hypertrophy.

Animals↗
PubMed2006

Surviving cell death through epidermal growth factor (EGF) signal transduction pathways: implications for cancer therapy.

There is a balance between cell death and survival in living organisms. The ability of cells to sense their environment and decide to survive or die is dependent largely upon growth factors. Epidermal growth factor (EGF) is a key growth factor regulating cell survival. Through its binding to cell surface receptors, EGF activates an extensive network of signal transduction pathways that include activation of the PI3K/AKT, RAS/ERK and JAK/STAT pathways. These pathways predominantly lead to activation or inhibition of transcription factors that regulate expression of both pro- and anti-apoptotic proteins effectively blocking the apoptotic pathway. In cancer, EGF signaling pathways are often dysfunctional and targeted therapies that block EGF signaling have been successful in treating cancers. In this review, we will discuss the EGF survival signaling network, how it cross-talks with the apoptotic signaling pathways and the therapeutic drugs targeting the EGF survival pathway used to treat cancers.

Animals↗
PubMed2004

The Arabidopsis thaliana chloroplast proteome reveals pathway abundance and novel protein functions.

BACKGROUND: Chloroplasts are plant cell organelles of cyanobacterial origin. They perform essential metabolic and biosynthetic functions of global significance, including photosynthesis and amino acid biosynthesis. Most of the proteins that constitute the functional chloroplast are encoded in the nuclear genome and imported into the chloroplast after translation in the cytosol. Since protein targeting is difficult to predict, many nuclear-encoded plastid proteins are still to be discovered. RESULTS: By tandem mass spectrometry, we identified 690 different proteins from purified Arabidopsis chloroplasts. Most proteins could be assigned to known protein complexes and metabolic pathways, but more than 30% of the proteins have unknown functions, and many are not predicted to localize to the chloroplast. Novel structure and function prediction methods provided more informative annotations for proteins of unknown functions. While near-complete protein coverage was accomplished for key chloroplast pathways such as carbon fixation and photosynthesis, fewer proteins were identified from pathways that are downregulated in the light. Parallel RNA profiling revealed a pathway-dependent correlation between transcript and relative protein abundance, suggesting gene regulation at different levels. CONCLUSIONS: The chloroplast proteome contains many proteins that are of unknown function and not predicted to localize to the chloroplast. Expression of nuclear-encoded chloroplast genes is regulated at multiple levels in a pathway-dependent context. The combined shotgun proteomics and RNA profiling approach is of high potential value to predict metabolic pathway prevalence and to define regulatory levels of gene expression on a pathway scale.

Arabidopsis↗
PubMed2004

Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.

In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.

Adipose Tissue↗
PubMed2006

The fat cadherin acts through the hippo tumor-suppressor pathway to regulate tissue size.

BACKGROUND: The Hippo tumor-suppressor pathway has emerged as a key signaling pathway that controls tissue size in Drosophila. Merlin, the Drosophila homolog of the human Neurofibromatosis type-2 (NF2) tumor-suppressor gene, and the related protein Expanded are the most upstream components of the Hippo pathway identified so far. However, components acting upstream of Expanded and Merlin, such as transmembrane receptors, have not yet been identified. RESULTS: Here, we report that the protocadherin Fat acts as an upstream component in the Hippo pathway. Fat is a known tumor-suppressor gene in Drosophila, and fat mutants have severely overgrown imaginal discs. We found that the overgrowth phenotypes of fat mutants are similar to those of mutants in Hippo pathway components: fat mutant cells continued to proliferate after wild-type cells stopped proliferating, and fat mutant cells deregulated Hippo target genes such as cyclin E and diap1. Fat acts genetically and biochemically upstream of other Hippo pathway components such as Expanded, the Hippo and Warts kinases, and the transcriptional coactivator Yorkie. Fat is required for the stability of Expanded and its localization to the plasma membrane. In contrast, Fat is not required for Merlin localization, and Fat and Merlin act in parallel in growth regulation. CONCLUSIONS: Taken together, our data identify a cell-surface molecule that may act as a receptor of the Hippo signaling pathway.

Animals↗
PubMed2006

Fat cadherin modulates organ size in Drosophila via the Salvador/Warts/Hippo signaling pathway.

BACKGROUND: The atypical Fat cadherin has long been known to control cell proliferation and organ size in Drosophila, but the mechanism by which Fat controls these processes has remained elusive. A newly emerging signaling pathway that controls organ size during development is the Salvador/Warts/Hippo pathway. RESULTS: Here we demonstrate that Fat limits organ size by modulating activity of the Salvador/Warts/Hippo pathway. ft interacts genetically with positive and negative regulators of this pathway, and tissue lacking fat closely phenocopies tissue deficient for genes that normally promote Salvador/Warts/Hippo pathway activity. Cells lacking fat grow and proliferate more quickly than their wild-type counterparts and exhibit delayed cell-cycle exit as a result of elevated expression of Cyclin E. fat mutant cells display partial insensitivity to normal developmental apoptosis cues and express increased levels of the anti-apoptotic DIAP1 protein. Collectively, these defects lead to increased organ size and organism lethality in fat mutant animals. Fat modulates Salvador/Warts/Hippo pathway activity by promoting abundance and localization of Expanded protein at the apical membrane of epithelial tissues. CONCLUSIONS: Fat restricts organ size during Drosophila development via the Salvador/Warts/Hippo pathway. These studies aid our understanding of developmental organ size control and have implications for human hyperproliferative disorders, such as cancers.

Animals↗
PubMed2004

Interleukin-1beta can mediate growth arrest and differentiation via the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells.

Interleukin-1beta (IL-1beta) is a pleiotropic cytokine that can induce several cellular signal transduction pathways. Here, we show that IL-1beta can induce cell cycle arrest and differentiation in the human medullary thyroid carcinoma (MTC) cell line, TT. IL-1beta induces cell cycle arrest accompanied by morphological changes and expression of the neuroendocrine marker calcitonin. These changes are blocked by the MEK1/2 specific inhibitor U0126, indicating that MEK1/2 is essential for IL-1beta signaling in TT cells. IL-1beta induces expression of leukemia inhibitory factor (LIF) and activation of STAT3 via the MEK/ERK pathway. This activation of STAT3 could be abrogated by treatment with anti-LIF neutralizing antibody or anti-gp130 blocking antibody, indicating that induction of LIF expression is sufficient and essential for STAT3 activation by IL-1beta. In addition to activation of the LIF/JAK/STAT pathway, IL-1beta also induced an MEK/ERK-mediated intracellular cell-autonomous signaling pathway that is independently sufficient for growth arrest and differentiation. Thus, IL-1beta activates the MEK/ERK pathway to induce growth arrest and differentiation in MTC cells via dual independent signaling mechanisms, the cell-extrinsic LIF/JAK/STAT pathway, and the cell-intrinsic autonomous signaling pathway.

Antigens, CD↗
PubMed2005

Is the activation potential of Mahaim pathway always a fast potential? Implication for radiofrequency catheter ablation.

INTRODUCTION: Accessory pathways (AP) exhibiting Mahaim physiology are amenable to radiofrequency (RF) catheter ablation. The recording of an AP potential is an excellent guide for selection of ablation site. The purpose of this study is to determine whether the pathway potential is always a fast potential. METHODS: Ten patients (six females, mean age, 30 +/- 12 years) with preexcited tachycardias involving a Mahaim pathway underwent electrophysiological study and subsequent attempts at RF ablation. Mahaim potentials (M-potential) recorded at the site of successful ablation were reviewed and classified by at least two reviewers. RESULTS: In all patients, Mahaim pathways were characterized as atriofascicular types. The M-potential was fast in seven patients (group one), and slow in the remaining patients (group two). All group two patients had a history of prior failed ablation. Atrial electrograms were recorded closer to the QRS onset in group one. Atrium to fast M-potential (42 +/- 15 ms) was shorter than atrium to slow M-potential (83 +/- 12 ms, P = 0.03) but M-potentials were recorded with similar distance before local ventricular electrogram (P = NS). Ablation was successful in all patients with mean of 2.9 +/- 1.4 RF applications per patient. Ablation data were similar between the two groups (P = NS). No complications occurred. During 12 months of follow-up, no recurrence was observed. CONCLUSION: Our results illustrated that the activation potential of Mahaim pathways is not always a fast potential. One-third of Mahaim pathways can be mapped and ablated when the slow type of M-potential was used as a target for ablation. We also confirmed high efficacy of catheter ablation of Mahaim pathways guided by activation potentials.

Adolescent↗
PubMed2004

Human alphaA- and alphaB-crystallins prevent UVA-induced apoptosis through regulation of PKCalpha, RAF/MEK/ERK and AKT signaling pathways.

AlphaA- and alphaB-crystallins are distinct antiapoptotic regulators. Regarding the antiapoptotic mechanisms, we have previously demonstrated that under staurosporine treatment, HalphaA- and HalphaB-crystallins can interact with Bax and Bcl-XS, proapoptotic members of the Bcl-2 family, to sequester their translocation into mitochondria, and thus prevent the staurosporine-induced apoptosis. In the present study, we further compared the anti-apoptotic mechanisms of HalphaA- and HalphaB-crystallin in preventing human lens epithelial cells from UVA-induced apoptosis. UVA-irradiation of human lens epithelial cells turned on the apoptotic death program. Moreover, associated with the activation of the death program, UVA also activated the RAF/MEK/ERK signaling pathway. In contrast, p38 kinase and JNK1/2 signaling pathways were not activated. Inhibition of the RAF/MEK/ERK pathway by a dominant negative mutant RAF1 greatly attenuated UVA-induced apoptosis. Expression of the exogenous human alphaB-crystallin prevented UVA-induced activation of RAF/MEK/ERK pathway and thus substantially abrogated UVA-induced apoptosis. In contrast, expression of the exogenous human alphaA-crystallin did not prevent UVA-induced activation of RAF/MEK/ERK pathway. Instead, it activated AKT kinase pathway to promote survival and thus counteracted the UVA-induced apoptosis. Together, our results for the first time reveal that by regulating multiple signaling pathways the two alpha-crystallins can prevent stress-induced apoptosis through different mechanisms.

Apoptosis↗
PubMed2006

Reconstruction and in silico analysis of the MAPK signaling pathways in the human blood fluke, Schistosoma japonicum.

At present, little is known about signal transduction mechanisms in schistosomes, which cause the disease of schistosomiasis. The mitogen-activated protein kinase (MAPK) signaling pathways, which are evolutionarily conserved from yeast to Homo sapiens, play key roles in multiple cellular processes. Here, we reconstructed the hypothetical MAPK signaling pathways in Schistosoma japonicum and compared the schistosome pathways with those of model eukaryote species. We identified 60 homologous components in the S. japonciumMAPK signaling pathways. Among these, 27 were predicted to be full-length sequences. Phylogenetic analysis of these proteins confirmed the evolutionary conservation of the MAPK signaling pathways. Remarkably, we identified S. japonicum homologues of GTP-binding protein beta and alpha-I subunits in the yeast mating pathway, which might be involved in the regulation of different life stages and female sexual maturation processes as well in schistosomes. In addition, several pathway member genes, including ERK, JNK, Sja-DSP, MRAS and RAS, were determined through quantitative PCR analysis to be expressed in a stage-specific manner, with ERK, JNK and their inhibitor Sja-DSP markedly upregulated in adult female schistosomes.

Amino Acid Sequence↗
PubMed2006

Death pathways in noise-damaged outer hair cells.

Using morphological criteria, death pathways in outer hair cells (OHCs) were determined in chinchilla organs of Corti that had been exposed to a high- or moderate-level octave band of noise (OBN) centered at either 0.5 or 4-kHz. The specimens were part of our large collection of plastic-embedded flat preparations of chinchilla cochleae. Three death pathways were identified: (1) oncotic - swollen, pale-staining cell with a swollen nucleus, (2) apoptotic - shrunken, dark-staining cell with a pyknotic nucleus and (3) a newly defined third pathway - no basolateral plasma membrane but cellular debris arranged in the shape of an intact OHC with a nucleus deficient in nucleoplasm. To minimize the secondary loss of OHCs from the entrance of endolymph into the organ of Corti, the specimens used for quantitative analysis of death pathways had the following characteristics: (1) the level to which they were exposed was less than or equal to 95dB SPL, (2) the exposure duration was 6-216h, (3) fixation for microscopic examination took place in vivo 1-2h post-exposure and (4) there were no focal OHC lesions in the organs of Corti. Fifty-eight noise-exposed cochleae met these criteria. In these specimens, degenerating and missing OHCs were classified as to which death pathway the cells had followed or were following. Nine non-noise-exposed cochleae were also evaluated for OHC death pathways. The number of OHCs following the third death pathway was significantly greater in the noise-exposed cochleae than the non-noise-exposed cochleae for total exposure energies greater than those produced by 75dB SPL for 216h to a 0.5-kHz OBN and 57dB SPL for 48h to a 4-kHz OBN. In cochleae exposed to either octave band, OHCs dying by oncosis or apoptosis were uncommon.

Animals↗
PubMed2005

Activation of the canonical Wnt/beta-catenin pathway confers growth advantages in c-Myc/E2F1 transgenic mouse model of liver cancer.

BACKGROUND/AIMS: Previously, we showed that activation of the beta-catenin/Wnt pathway is a dominant event during c-Myc/E2F1 hepatocarcinogenesis. Majority of c-Myc/E2F1 HCCs displayed nuclear accumulation of beta-catenin in the absence of beta-catenin mutations, suggesting that alterations in other members of the Wnt pathway might be responsible for nuclear localization of beta-catenin. Here, we investigated the mechanisms responsible for nuclear translocation of wild-type beta-catenin and addressed the potential contribution of the Wnt pathway in c-Myc/E2F1 hepatocarcinogenesis. METHODS: Status of the members of the Wnt pathway was determined through microsatellite and Western blot analysis. RESULTS: Majority of c-Myc/E2F1 HCCs exhibited multiple abnormalities in the Wnt pathway regardless of the presence of beta-catenin mutations. The observed abnormalities included overexpression of Wnt-1, Frizzled 1 and 2 receptors, Dishevelled-1, downregulation of Secreted frizzled-related protein-1, GSK-3beta inactivation, microsatellite instability at the Axin locus as well as induction of beta-catenin target genes, such as glutamine synthetase, glutamate transporter-1, and Wisp-1. HCCs with beta-catenin activation displayed significantly higher proliferation rate and larger tumor size when compared with beta-catenin negative tumors. CONCLUSIONS: The data demonstrate that multiple abnormalities in the members of the Wnt pathway lead to nuclear accumulation of beta-catenin and suggest that activation of Wnt pathway provides proliferative advantages in c-Myc/E2F1-driven hepatocarcinogenesis.

Animals↗
PubMed2005

Symmetric connectivity of secondary structure elements enhances the diversity of folding pathways.

The influence of native connectivity of secondary structure elements (SSE) on folding is studied using coarse-grained models of proteins with mixed alpha and beta structure and the analysis of the structural database of wild-type proteins. We found that the distribution of SSE along a sequence determines the diversity of folding pathways. If alpha and beta SSE are localized in different parts of a sequence, the diversity of folding pathways is restricted. An even (symmetric) distribution of alpha and beta SSE with respect to sequence midpoint favors multiple folding routes. Simulations are supplemented by the database analysis of the distribution of SSE in wild-type protein sequences. On an average, two-thirds of wild-type proteins with mixed alpha and beta structure have symmetric distribution of alpha and beta SSE. The propensity for symmetric distribution of SSE is especially evident for large proteins with the number of SSE > or = 10. We suggest that symmetric SSE distribution in protein sequences may arise due to nearly random allocation of alpha and beta structure along wild-type sequences. The tendency of long sequences to misfold is perhaps compensated by the enhanced pathway diversity. In addition, folding pathways are shown to progress via hierarchic assembly of SSE in accordance with their proximity along a sequence. We demonstrate that under mild denaturation conditions folding and unfolding pathways are similar. However, the reversibility of folding/unfolding pathways is shown to depend on the distribution of SSE. If alpha and beta SSE are localized in different parts of a sequence, folding and unfolding pathways are likely to coincide.

Computer Simulation↗
PubMed2005

Inferring meaningful pathways in weighted metabolic networks.

An approach is presented for computing meaningful pathways in the network of small molecule metabolism comprising the chemical reactions characterized in all organisms. The metabolic network is described as a weighted graph in which all the compounds are included, but each compound is assigned a weight equal to the number of reactions in which it participates. Path finding is performed in this graph by searching for one or more paths with lowest weight. Performance is evaluated systematically by computing paths between the first and last reactions in annotated metabolic pathways, and comparing the intermediate reactions in the computed pathways to those in the annotated ones. For the sake of comparison, paths are computed also in the un-weighted raw (all compounds and reactions) and filtered (highly connected pool metabolites removed) metabolic graphs, respectively. The correspondence between the computed and annotated pathways is very poor (<30%) in the raw graph; increasing to approximately 65% in the filtered graph; reaching approximately 85% in the weighted graph. Considering the best-matching path among the five lightest paths increases the correspondence to 92%, on average. We then show that the average distance between pairs of metabolites is significantly larger in the weighted graph than in the raw unfiltered graph, suggesting that the small-world properties previously reported for metabolic networks probably result from irrelevant shortcuts through pool metabolites. In addition, we provide evidence that the length of the shortest path in the weighted graph represents a valid measure of the "metabolic distance" between enzymes. We suggest that the success of our simplistic approach is rooted in the high degree of specificity of the reactions in metabolic pathways, presumably reflecting thermodynamic constraints operating in these pathways. We expect our approach to find useful applications in inferring metabolic pathways in newly sequenced genomes.

Amino Acids↗
PubMed2005

Evaluation of pathways for progression of heterogeneous breast tumors.

To better understand the progression of heterogeneous breast cancers, four models of progession pathways have been evaluated. The models describe the progression through the grades of ductal carcinoma in situ (DCIS) 1, 2, and 3, and through the grades of invasive ductal carcinoma (IDC) 1, 2, and 3. The first three pathways, termed linear, nonlinear, and branched, describe DCIS as a progenitor of IDC, and grades of DCIS progressing into grades of IDC. The fourth pathway, termed parallel, describes DCIS and IDC as diverging from a common progenitor and progressing through grades in parallel. The best transition rates for the linear, nonlinear, and branched pathways were sought using a random search in combination with a directed search based on the Nelder-Mead simplex method. Parameter values for the parallel pathway were determined with heuristic graphs. Results of computer simulation were compared with clinically observed frequencies of grades of DCIS and grades of IDC that were reported to occur together in heterogeneous tumors. Each of the four pathways could simulate frequencies that resembled, to varying degrees, the clinical observations. The parallel pathway produced the best correspondence with clinical observations. These results quantify the traditional descriptions in which grades of DCIS are the progenitors of grades of IDC. The results also raise the alternative possibility that, in some tumors with both components, DCIS and IDC may have diverged from a common progenitor.

Algorithms↗
PubMed2005

Spontaneous polarization in eukaryotic gradient sensing: a mathematical model based on mutual inhibition of frontness and backness pathways.

A key problem of eukaryotic cell motility is the signaling mechanism of chemoattractant gradient sensing. Recent experiments have revealed the molecular correlate of gradient sensing: Frontness molecules, such as PI3P and Rac, localize at the front end of the cell, and backness molecules, such as Rho and myosin II, accumulate at the back of the cell. Importantly, this frontness-backness polarization occurs spontaneously even if the cells are exposed to uniform chemoattractant profiles. The spontaneous polarization suggests that the gradient sensing machinery undergoes a Turing bifurcation. This has led to several classical activator-inhibitor and activator-substrate models which identify the frontness molecules with the activator. Conspicuously absent from these models is any accounting of the backness molecules. This stands in sharp contrast to experiments which show that the backness pathways inhibit the frontness pathways. Here, we formulate a model based on the mutually inhibitory interaction between the frontness and backness pathways. The model builds upon the mutual inhibition model proposed by Bourne and coworkers [Xu et al., 2003. Divergent signals and cytoskeletal assemblies regulate self-organizing polarity in neutrophils. Cell 114, 201-214.]. We show that mutual inhibition alone, without the help of any positive feedback (autocatalysis), can trigger spontaneous polarization of the frontness and backness pathways. The spatial distribution of the frontness and backness molecules in response to inhibition and activation of the frontness and backness pathways are consistent with those observed in experiments. Furthermore, depending on the parameter values, the model yields spatial distributions corresponding to chemoattraction (frontness pathways in-phase with the external gradient) and chemorepulsion (frontness pathways out-of-phase with the external gradient). Analysis of the model suggests a mechanism for the chemorepulsion-to-chemoattraction transition observed in neurons.

Animals↗