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PubMed2004

Calcium signaling in chemorepellant Slit2-dependent regulation of neuronal migration.

Migration of neuronal precursor cells in the developing brain is guided by extracellular cues, but intracellular signaling processes underlying the guidance of neuronal migration are largely unknown. By examining the migration of cerebellar granule neurons along the surface of cocultured astroglial cells, we found that an extracellular gradient of Slit2, a chemorepellant for neuronal migration in vivo, caused a reversal in the direction of migration without affecting the migration speed. A Slit2 gradient elevated the intracellular concentration of Ca2+, probably due to calcium release from the internal store, led to a reversal of the preexisting asymmetric intracellular Ca2+ distribution in the soma of migrating neurons, and this reversal was closely related with its action of reversing the migrating direction. Asymmetric Ca2+ distribution in the soma was both necessary and sufficient for directing neuronal migration. These results have demonstrated an important role for Ca2+ in mediating neuronal responses to Slit2 and suggest a general mechanism for neuronal guidance.

Animals↗
PubMed2004

Single-molecule study of RuvAB-mediated Holliday-junction migration.

Branch migration of Holliday junctions is an important step of genetic recombination and DNA repair. In Escherichia coli, this process is driven by the RuvAB complex acting as a molecular motor. Using magnetic tweezers, we studied the RuvAB-directed migration of individual Holliday junctions formed between two approximately 6-kb DNA molecules of identical sequence, and we measured the migration rate at 37 degrees C and 1 mM ATP. We directly demonstrate that RuvAB is a highly processive DNA motor protein that is able to drive continuous and unidirectional branch migration of Holliday junctions at a well defined average speed over several kilobases through homologous sequences. We observed directional inversions of the migration at the DNA molecule boundaries leading to forth-and-back migration of the branch point and allowing us to measure the migration rate in the presence of negative or positive loads. The average migration rate at zero load was found to be approximately 43 bp/sec. Furthermore, the load dependence of the migration rate is small, within the force range of -3.4 pN (hindering force) to +3.4 pN (assisting force).

Bacterial Proteins↗
PubMed1990

Central nervous system neurons migrate on astroglial fibers from heterotypic brain regions in vitro.

In different regions of the developing mammalian brain, neurons follow the processes of radial glial cells over very different trajectories to reach their destinations in specific neuronal layers. To investigate whether the movement of neurons along glial fibers is specified by glia in a given region or whether glia provide a permissive substrate for migration in different brain regions, we purified neurons and astroglial cells from developing cerebellum and hippocampus and analyzed neuronal migration on heterotypic glial fibers with time-lapse, video-enhanced differential interference microscopy in vitro. Granule neurons purified from early postnatal rat cerebellum migrated on astroglial processes of glia purified from late embryonic or early postnatal rat hippocampus with a cytology, neuron-glial relationship, and dynamics of movement that were indistinguishable from those of mouse granule cells migrating on cerebellar astroglial processes in vitro [Edmondson, J. C. & Hatten, M. E. (1987) J. Neurosci. 7, 1928-1934]. In the reciprocal combination, hippocampal neurons migrated on cerebellar glial processes in a manner that was also remarkably similar to migration along homotypic, hippocampal glial fibers [Gasser, U. E. & Hatten, M. E. (1990) J. Neurosci. 10, 1276-1285]. In all cases, migrating neurons had a characteristic appearance, apposing their cell soma against the glial fiber and extending in the direction of migration a motile, leading process that enfolded the glial fiber with short filopodia and lamellipodia. As seen by video microscopy, neurons moved along homotypic and heterotypic glial processes by translocation of the soma and were not "pulled" forward by the leading process. As the neuron moved, the nucleus remained in the posterior portion of the cell and cytoplasmic vesicles moved forward from the soma into the leading process. The dynamics of the movement of neurons along heterotypic glial substrates, including the speed and periodicity of motion, was identical to that of neurons migrating along homotypic glial substrates. These experiments suggest that the mechanism of movement of neurons along glial fibers is conserved in these two brain regions during development.

Animals↗
PubMed1994

Molecular analysis of cell surface beta-1,4-galactosyltransferase function during cell migration.

Despite the identification and characterization of cell surface receptors for the extracellular matrix, it is unknown how their relative expression and cytoskeletal association regulate cell migration. Previous studies have identified beta-1,4-galactosyltransferase (GalTase; EC 2.4.1.38) on the surface of migrating cells, where it mediates cell migration on basal lamina matrices by associating with the cytoskeleton and binding to N-linked oligosaccharides in the E8 domain of laminin. In this study, the function of GalTase during cell migration was examined directly by analyzing the migration rate of stably transfected cell lines in which the relative level of surface GalTase and its ability to associate with the cytoskeleton were altered. We show here that the cytoskeleton contains a limiting, saturable, number of binding sites for surface GalTase. Furthermore, the rate of cell migration was inversely related to the ability of surface GalTase to associate with the cytoskeleton. Elevating surface GalTase in excess of the number of cytoskeleton-binding sites reduced the rate of cell migration, whereas decreasing the amount of surface GalTase available to bind the cytoskeleton increased migration rates. These results show that the rate of cell migration on basal lamina is directly dependent upon the expression of surface GalTase and the ability of this protein to associate with a limiting number of cytoskeleton-binding sites.

3T3 Cells↗
PubMed2001

Membrane type 1-matrix metalloproteinase is activated during migration of human endothelial cells and modulates endothelial motility and matrix remodeling.

Matrix metalloproteinases are thought to play an important role in endothelial cell migration and matrix remodeling. We have used an in vitro wound healing migration model and newly generated anti-membrane type 1-matrix metalloproteinase (MT1-MMP) monoclonal antibodies (mAbs) to characterize the role of MT1-MMP during this process. First, the expression and shedding of MT1-MMP are up-regulated upon induction of migration in endothelial cells, as demonstrated by flow cytometry and Western blot analysis. Furthermore, MT1-MMP is concentrated at discrete areas in migrating endothelial cells, in contrast to the diffuse pattern observed in confluent cells. Interestingly, migration of endothelial cells results in the stimulation of MT1-MMP activity, as shown by its ability to process pro-MMP-2 and to degrade fibrinogen assessed by zymography. Moreover, MT1-MMP-mediated gelatin degradation is enriched at migration sites. mAbs generated against the MT1-MMP catalytic domain are shown to inhibit MT1-MMP enzymatic activity and to impair both phorbol 12-myristate 13-acetate-induced endothelial migration and invasion of collagen and fibrin gels. Furthermore, a reduction in the formation of capillary tubes in Matrigel is also observed when endothelial cells are pretreated with the blocking anti-MT1-MMP mAbs. Altogether, these data demonstrate that MT1-MMP plays an important role during endothelial cell migration, and its activity can modulate endothelial migration, invasion, and formation of capillary tubes during the angiogenic response.

Antibodies, Monoclonal↗
PubMed2005

WAVE3-mediated cell migration and lamellipodia formation are regulated downstream of phosphatidylinositol 3-kinase.

WAVE3 is a member of the WASP/WAVE family of protein effectors of actin reorganization and cell movement. The precise role of WAVE3 in cell migration and its regulation, however, have not been elucidated. Here we show that endogenous WAVE3 was found to be concentrated in the lamellipodia at the leading edge of migrating MDA-MB-231 cells. Platelet-derived growth factor (PDGF) treatment induced lamellipodia formation as well as two-dimensional migration of cells in the wound-closure assay and chemotactic migration toward PDGF in three-dimensional migration chambers. Knockdown of WAVE3 expression by RNA interference prevented the PDGF-induced lamellipodia formation and cell migration. Treatment of cells with LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), also abrogated the PDGF-induced lamellipodia formation and cell migration, suggesting that PI3K may be required for WAVE3 activity. WAVE3 and the PI3K regulatory subunit, p85, were found to interact in a yeast two-hybrid screen, which was confirmed through co-immunoprecipitation. The WAVE3-p85 interaction was mediated by the N-terminal region of WAVE3 and the C-terminal SH2 domain of p85. These results imply that the WAVE3-mediated migration in MDA-MB-231 cells via lamellipodia formation is activated downstream of PI3K and induced by PDGF. The findings of the WAVE3-p85 partnership also suggest a potential regulatory role for p85 in WAVE3-dependent actin-cytoskeleton reorganization and cell migration.

Actins↗
PubMed2005

Ca2+ influx through L-type Ca2+ channels controls the trailing tail contraction in growth factor-induced fibroblast cell migration.

Growth factor-induced cell migration underlies various physiological and pathological processes. The mechanisms by which growth factors regulate cell migration are not completely understood. Although intracellular elevation of Ca2+ is known to be critical in cell migration, the source of this Ca2+ elevation and the mechanism by which Ca2+ modulates this process in fibroblast cells are not well defined. Here we show that increase of cellular Ca2+ through Ca2+ influx, rather than Ca2+ release from intracellular stores, is essential for growth factor-induced fibroblast cell migration. Voltage-gated L-type Ca2+ channels, previously known to exist in excitable cells such as neurons and muscle cells, are shown here to be present in fibroblasts as well. Furthermore, these channels are responsible for the Ca2+ influx. L-type Ca2+ channel inhibitors block growth factor-induced Ca2+ influx and fibroblast cell migration. One mechanism by which Ca2+ signals control cell migration is to regulate the contraction of the trailing edge of migrating fibroblasts; this process is controlled by the small GTPase Rho in fast migrating cells such as leukocytes. Downstream of Ca2+, both calmodulin and myosin light chain kinase, but not calcineurin, are involved leading to phosphorylation of the myosin light chain at the trailing end. Thus, trailing edge contraction is critically regulated by Ca2+ influx through L-type Ca2+ channels in growth factor-induced fibroblast cell migration.

Animals↗
PubMed2005

Investigation of the lateral light-induced migration of photosystem II light-harvesting proteins by nano-high performance liquid chromatography electrospray ionization mass spectrometry.

This study reports a detailed analysis of the light-induced lateral migration of the photosystem II (PSII) antennae between appressed and non-appressed thylakoid membranes. The relative PSII antennae that migrated to stroma lamellae were readily established on the basis of peak areas of the separated stroma proteins in the ultraviolet chromatograms. Phosphorylation was predicted by intact molecular mass measurements, and this was confirmed by immunoblotting. When thylakoid membrane and chloroplasts were illuminated at 100 microE m(-2)s(-1), light-harvesting complex type II (Lhcb2) was the first PSII antenna to migrate, preferentially in phosphorylated form. However, the amount of Lhcb2 that migrated decreased after the first 20 min when the total amount of the three different Lhcb1 isoforms (1.1, 1.2, and 1.3) reached maximum. Lhcb1.1 was always found in the unphosphorylated form and migrated later than the other two isoforms, although the latter were also found to have low levels of phosphorylation. At the same time, major antennae on the grana were not found to be phosphorylated, whereas Lhcb4 showed a significant increase in molecular mass. At higher light intensity Lhcb2 migration was negligible, whereas migration of Lhcb1 isoforms was little changed, increasing in irradiated chloroplasts. Because there was no significant phosphorylation at high light intensity, and yet pigments were found to have significantly increased on the stroma lamellae, it may be that pigments play a role in migration and that, in fact, there is no direct correlation between phosphorylation and migration. We hypothesize that the Lhcb1 isoforms expressed by the multigene families play a role in plant adaptation.

Chloroplasts↗
PubMed1997

Human corneal epithelial cells reorient and migrate cathodally in a small applied electric field.

PURPOSE: To test whether human corneal epithelial cells (HCECs) respond to small applied electric fields (EFs) in a similar manner to bovine corneal epithelial cells (BCECs), the orientation and directed migration in small EFs of both primary cultures and of a human corneal epithelial cell line were quantified. METHODS: Primary cultures of human corneal epithelial cells (PHCECs) and transformed human corneal epithelial cells (THCECs) were exposed to EFs (100 mV/mm-250 mV/mm) in different media. Cell migration was traced using an image analyser. RESULTS: PHCECs and THCECs reoriented and migrated towards the cathode (negative pole) when cultured in small direct current (dc) EFs. Both the reorientation and directional migration were voltage- and serum-dependent, as shown previously for bovine cells. PHCECs and THCECs showed significant perpendicular orientation in EFs at 150 mV/mm in medium with serum, while at the same voltage, no significant orientation was found in serum free medium. PHCECs started to show perpendicular reorientation around 30 min after onset of EF at 150 mV/mm. They showed significant directional migration at 150 mV/mm, with directedness of 0.35 +/- 0.07 and a migration rate of 9.1 +/- 0.7 microns/h (n = 90), both significantly higher than that of cells in serum free medium. Addition of EGF-induced significant reorientation and directional migration of THCECs at 100 mV/mm. Additionally, as for BCECs, which remained viable and responsive to electric fields for at least 75 h at 150 mV/mm, THCECs also remained viable and showed responsiveness during long periods of exposure to EFs (at least 20 h). CONCLUSIONS: Cultured human primary CECs and a human corneal epithelial cell line both responded to small EFs with perpendicular reorientation and cathodally-directed migration. Cell responses were qualitatively similar to those reported previously for bovine CECs. The endogenous EFs generated by wounded cornea may play an important role in promoting cell shape changes and directed migration of CECs during the healing process.

Animals↗
PubMed2001

Impaired sensitivity to beta 2 integrin-blocking in ICAM-1-mediated neutrophil migration in ulcerative colitis.

BACKGROUND: Factors influencing the directed migration of neutrophils into colonic tissue in ulcerative colitis (UC) are poorly described. ICAM-1 has recently been shown to possess chemotactic properties, and the aim of this study was to evaluate the involvement of beta 2 integrins in this ICAM-1-mediated migration. METHODS: The chemotactic effect of ICAM-1 on neutrophils isolated from 13 UC patients and 17 healthy volunteers was studied in microchemotaxis chambers. Physiological concentrations of ICAM-1 (0.05-500 pM) were separated from neutrophils by nitrocellulose filters, and cell migration was evaluated using the leading front technique. beta 2 integrins on neutrophils were blocked with antibodies to CD11a, CD11b, CD11c and CD18, and migration towards ICAM-1 was examined. RESULTS: Migration towards ICAM-1 was equal for UC and control neutrophils, showing a bell-shaped ICAM-1 dosemigratory response curve with peak migration at 5 pM ICAM-1 (30.0 microns; interquartile range 22.9-35.7; P < 0.001). Blockade of the CD11 subunits on control cells inhibited the chemoattractant effect of ICAM-1 by 43.6%-58.0%, whereas the migration was decreased by only 20% in UC under similar blocking conditions (P < 0.01). Anti-CD18 mAbs had no effect. Inhibition of protein kinases with staurosporin only slightly decreased the ICAM-1-mediated migration, whereas incubation with staurosporin and CD11 antibodies showed additive effects on UC neutrophils and synergistic effects on control cells. No quantitative differences in beta 2 integrin expression were detected between control and UC neutrophils. CONCLUSIONS: The chemotactic property of ICAM-1 was shown to be CD11-dependent and UC neutrophils were found to be less dependent on CD11/ICAM-1-mediated migration than were control neutrophils.

Adult↗
PubMedDate not supplied

Migration of 3T3 and lung fibroblasts in response to calcitonin gene-related peptide and bombesin.

Neuropeptides found in airways, such as bombesin and calcitonin gene-related peptide (CGRP), are known to elicit proliferation of several cell types, including fibroblasts and epithelial cells in culture and in vivo. However, the effects of these neuropeptides on fibroblast migration, which may also be a necessary part of airway repair, have not been well established. To determine if these peptides could stimulate fibroblast chemotaxis, we grew NIH 3T3 and IM R-90 cells in culture and studied migration using 48-well blindwell chambers. 3T3 cells were treated with 10(-14) to 10(-7) M bombesin or 10(-14) to 10(-7) M CGRP and permitted to migrate through a gelatin-coated filter for 2-24 hours. Both bombesin and CGRP elicited 3T3 migration which was both time and concentration dependent. After 6 hours, migration of 3T3 cells treated with 10(-7) M bombesin was 33.9 +/- 4.4 cells versus control migration of 4.0 +/- 1.2 cells per 10 high-power fields (hpf) (P < .01, n = 4). Migration of 3T3 cells treated with 10(-9) M CGRP was 30.2 +/- 5.4 cells versus control migration of 10.7 +/- 1.4 cells per 10 hpf (P < 0.02, n = 6). IMR-90 cells migrated in a similar manner in response to CGRP and bombesin. The response to each neuropeptide was both chemotactic and chemokinetic, and could be blocked completely with an appropriate receptor antagonist. We demonstrate that both bombesin and CGRP are chemotactic for 3T3 and IMR-90 fibroblasts in culture. These peptides therefore may have multiple roles in repair and healing of airway injury.

3T3 Cells↗
PubMed2004

Migration of inorganic contaminants into dry food from packaging made from recycled paper and board.

A radiotracer method was applied to the measurement of inorganic contaminants migrating into food. The method was applied to the study of 10 samples of recycled paper and board. The only elements detected in the static migration test were zinc and iron, at concentrations close to the detection limit. Samples of rice, oats, custard powder, mushrooms and fries showed that traces of these elements had migrated from the packaging. The migration was limited to less than 1%, with the exception of the mushrooms, where the decomposition of the food had resulted in a 12.5% transfer of zinc from the mushroom bag after 8 days, equivalent to migration of 0.022 mg dm(-2). Shaking had no effect on migration, except in one case of custard powder where migration occurred at a level equivalent to 0.002 mg dm(-2). The maximum migration determined in the present study was 4.8 microg zinc and 2.6 microg iron, which is negligible when compared with the recommended daily intakes of 15 and 14 mg, respectively. When Tenax was tested as a food simulant, no zinc was detected (< 0.001 mg dm(-2)), although slight migration (0.001 mg dm(-2)) occurred into food.

Conservation of Natural Resources↗
PubMed2006

Approach to stochastic modelling of consumer exposure for any substance from canned foods using simulant migration data.

A two-dimensional probabilistic model was constructed to estimate the short-term dietary exposure of UK consumers to any generalized migrant from coated light metal food packaging. Using three UK National Dietary and Nutrition Surveys (NDNS) comprising 4-7-day dietary surveys for different age and gender groups, actual body weights and survey years, a sample representative of the dietary consumption of the UK population was obtained comprising around 4,200 food items. Interrogation of the raw data showed that the per capita consumption of food and beverage for an adult was 2.9 kg per person day(-1), which is comparable with the US FDA value of 3.0 kg. The packaging type of each food item was assigned from the survey descriptions or by sampling from distributions based upon market share information and expert judgement. Each food item was assigned to the relevant food simulant: A (aqueous), B (acidic) or D (fatty), so that simulant migration data could be used. The exposure model was used to evaluate exposure for a given level of migration and, conversely, the level of migration that could be tolerated whilst keeping within a target threshold exposure level. As examples, migration at 10 microg dm(-2) into fatty foods only resulted in an exposure ranging from 0.06 to 0.22 microg kg(-1) body (actual) weight day(-1) depending on the scenario. The model revealed that if migration from metal coatings was only into fatty foods, migration in the range 1.83-4.95 microg dm(2) (97.5th percentile, depending on the scenario) would give an exposure of less than 1.5 microg per person day(-1). This is a toxicological threshold limit used in the USA. If migration into simulants A and B is also considered to be at the same level as that for simulant D, then the level of migration for the threshold to be reached is, not surprisingly, lower (0.64-0.87 microg dm(-2)) than that if migration were only into fatty foods. In this case, clearly the main contributors to the exposure were foodstuffs represented by simulants A and B because of their importance in the diet. These estimates are based on 4- or 7-day food diaries and chronic exposure over the long-term would be expected to be lower.

Adolescent↗
PubMedDate not supplied

Migration testing with olive oil in a microwave oven.

A study was carried out to compare the overall migration from packaging materials into olive oil during heating in a microwave oven, and the overall migration from the same materials into olive oil but applying time and temperature conditions stipulated in the current EC and Dutch legislation on food packaging. Application of additional test conditions (e.g. 30 min and 1 h in combination with test temperatures exceeding 121 degrees C, and a test temperature of 130 degrees C) have demonstrated the need for extension of the test conditions mentioned in existing food packaging regulations to enable realistic migration testing of microwave packaging materials under conventional test conditions. It is concluded that the overall migration into olive oil from packaging materials intended for microwave oven use, including susceptor materials, can be judged on the basis of migration testing using conventional heating. For testing film or susceptor materials in a microwave oven by one-sided contact, a migration cell transparent to microwaves was developed and used up to 200 degrees C. In conventional high-temperature tests applying hot-filling of trays or migration cells, a temperature drop was observed, while handling oil at temperatures of 150 degrees-175 degrees C may be considered perilous. To prevent problems of this kind it is proposed to start migration tests at room temperature and to heat the simulant rapidly to the final test temperature. This procedure is comparable to migration tests carried out with aqueous food simulants at 121 degrees C in an autoclave.(ABSTRACT TRUNCATED AT 250 WORDS)

Food Contamination↗
PubMed1992

Cell surface beta 1,4-galactosyltransferase functions during neural crest cell migration and neurulation in vivo.

Mesenchymal cell migration and neurite outgrowth are mediated in part by binding of cell surface beta 1,4-galactosyltransferase (GalTase) to N-linked oligosaccharides within the E8 domain of laminin. In this study, we determined whether cell surface GalTase functions during neural crest cell migration and neural development in vivo using antibodies raised against affinity-purified chicken serum GalTase. The antibodies specifically recognized two embryonic proteins of 77 and 67 kD, both of which express GalTase activity. The antibodies also immunoprecipitated and inhibited chick embryo GalTase activity, and inhibited neural crest cell migration on laminin matrices in vitro. Anti-GalTase antibodies were microinjected into the head mesenchyme of stage 7-9 chick embryos or cranial to Henson's node of stage 6 embryos. Anti-avian GalTase IgG decreased cranial neural crest cell migration on the injected side but did not cross the embryonic midline and did not affect neural crest cell migration on the uninjected side. Anti-avian GalTase Fab crossed the embryonic midline and perturbed cranial neural crest cell migration throughout the head. Neural fold elevation and neural tube closure were also disrupted by Fab fragments. Cell surface GalTase was localized to migrating neural crest cells and to the basal surfaces of neural epithelia by indirect immunofluorescence, whereas GalTase was undetectable on neural crest cells prior to migration. These results suggest that, during early embryogenesis, cell surface GalTase participates during neural crest cell migration, perhaps by interacting with laminin, a major component of the basal lamina. Cell surface GalTase also appears to play a role in neural tube formation, possibly by mediating neural epithelial adhesion to the underlying basal lamina.

Animals↗
PubMed1998

Involvement of receptor-like protein tyrosine phosphatase zeta/RPTPbeta and its ligand pleiotrophin/heparin-binding growth-associated molecule (HB-GAM) in neuronal migration.

Pleiotrophin/heparin-binding growth-associated molecule (HB-GAM) is a specific ligand of protein tyrosine phosphatase zeta (PTPzeta)/receptor-like protein tyrosine phosphatase beta (RPTPbeta) expressed in the brain as a chondroitin sulfate proteoglycan. Pleiotrophin and PTPzeta isoforms are localized along the radial glial fibers, a scaffold for neuronal migration, suggesting that these molecules are involved in migratory processes of neurons during brain development. In this study, we examined the roles of pleiotrophin-PTPzeta interaction in the neuronal migration using cell migration assay systems with glass fibers and Boyden chambers. Pleiotrophin and poly-L-lysine coated on the substratums stimulated cell migration of cortical neurons, while laminin, fibronectin, and tenascin exerted almost no effect. Pleiotrophin-induced and poly-L-lysine-induced neuronal migrations showed significant differences in sensitivity to various molecules and reagents. Polyclonal antibodies against the extracellular domain of PTPzeta, PTPzeta-S, an extracellular secreted form of PTPzeta, and sodium vanadate, a protein tyrosine phosphatase inhibitor, added into the culture medium strongly suppressed specifically the pleiotrophin-induced neuronal migration. Furthermore, chondroitin sulfate C but not chondroitin sulfate A inhibited pleiotrophin-induced neuronal migration, in good accordance with our previous findings that chondroitin sulfate constitutes a part of the pleiotrophin-binding site of PTPzeta, and PTPzeta-pleiotrophin binding is inhibited by chondroitin sulfate C but not by chondroitin sulfate A. Immunocytochemical analysis indicated that the transmembrane forms of PTPzeta are expressed on the migrating neurons especially at the lamellipodia along the leading processes. These results suggest that PTPzeta is involved in the neuronal migration as a neuronal receptor of pleiotrophin distributed along radial glial fibers.

Animals↗
PubMed2001

Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins.

The L1 adhesion molecule plays an important role in axon guidance and cell migration in the nervous system. L1 is also expressed by many human carcinomas. In addition to cell surface expression, the L1 ectodomain can be released by a metalloproteinase, but the biological function of this process is unknown. Here we demonstrate that membrane-proximal cleavage of L1 can be detected in tumors and in the developing mouse brain. The shedding of L1 involved a disintegrin and metalloproteinase (ADAM)10, as transfection with dominant-negative ADAM10 completely abolishes L1 release. L1-transfected CHO cells (L1-CHO) showed enhanced haptotactic migration on fibronectin and laminin, which was blocked by antibodies to alpha v beta 5 and L1. Migration of L1-CHO cells, but not the basal migration of CHO cells, was blocked by a metalloproteinase inhibitor, indicating a role for L1 shedding in the migration process. CHO and metalloproteinase-inhibited L1-CHO cells were stimulated to migrate by soluble L1-Fc protein. The induction of migration was blocked by alpha v beta 5-specific antibodies and required Arg-Gly-Asp sites in L1. A 150-kD L1 fragment released by plasmin could also stimulate CHO cell migration. We propose that ectodomain-released L1 promotes migration by autocrine/paracrine stimulation via alpha v beta 5. This regulatory loop could be relevant for migratory processes under physiological and pathophysiological conditions.

Amyloid Precursor Protein Secretases↗
PubMed2004

Spermidine/spermine N1-acetyltransferase specifically binds to the integrin alpha9 subunit cytoplasmic domain and enhances cell migration.

The integrin alpha9beta1 is expressed on migrating cells, such as leukocytes, and binds to multiple ligands that are present at sites of tissue injury and inflammation. alpha9beta1, like the structurally related integrin alpha4beta1, mediates accelerated cell migration, an effect that depends on the alpha9 cytoplasmic domain. alpha4beta1 enhances migration through reversible binding to the adapter protein, paxillin, but alpha9beta1-dependent migration is paxillin independent. Using yeast two-hybrid screening, we identified the polyamine catabolizing enzyme spermidine/spermine N(1)-acetyltransferase (SSAT) as a specific binding partner of the alpha9 cytoplasmic domain. Overexpression of SSAT increased alpha9beta1-mediated migration, and small interfering RNA knockdown of SSAT inhibited this migration without affecting cell adhesion or migration that was mediated by other integrin cytoplasmic domains. The enzyme activity of SSAT is critical for this effect, because a catalytically inactive version did not enhance migration. We conclude that SSAT directly binds to the alpha9 cytoplasmic domain and mediates alpha9-dependent enhancement of cell migration, presumably by localized effects on acetylation of polyamines or of unidentified substrates.

Acetyltransferases↗