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PubMed2002

Deleted in colorectal carcinoma and differentially expressed integrins mediate the directional migration of neural precursors in the rostral migratory stream.

Precursors of the olfactory interneurons migrate from the subventricular zone via the rostral migratory stream (RMS). To investigate the molecular mechanisms by which RMS cells migrate, we used a slice preparation, which allows the migrating cells to be imaged at very high temporal and spatial resolution in the presence of added inhibitors. Using immunohistochemistry, we first determined that the alpha1-, beta8-, and beta1-integrin subunits and the alpha5- and gamma1-laminin subunits are expressed during embryonic day 16 to the early postnatal stage. During early postnatal days, alpha(v)- and beta6-integrins appeared, and their expression persisted throughout adulthood. The migrating cells also expressed the netrin receptors neogenin and Deleted in Colorectal Carcinoma (DCC). Netrin-1 is expressed in olfactory mitral cells. Anti-integrin antibodies inhibited the production of protrusions as well as cellular translocation. In contrast, anti-DCC antibodies primarily altered the direction of the protrusions; consequently, the migration was no longer unidirectional, and the speed was reduced. Thus, the interaction of DCC, possibly through an interaction with netrin-1, contributes to the direction of migration by regulating the formation of directed protrusions. In contrast, the integrins function in production of protrusions and cellular translocation, with different integrins participating at different developmental stages.

Aging↗
PubMed2002

Effect of extracellular matrix proteins on in vitro testosterone production by rat Leydig cells.

The aim of this study was to detect the effect of extracellular matrix (ECM) proteins on rat Leydig cell shape, adhesion, expression of integrin subunits and testosterone production, in vitro. Leydig cells isolated from adult rats were cultured on plates uncoated or coated with different concentrations of laminin-1, fibronectin, or type IV collagen in the presence or absence of hCG for 3 or 24 hr. A significant increase of cell adhesion and of alpha3, alpha5, and beta1 integrin subunit expression was observed when cells were cultured on ECM proteins, compared to those grown on uncoated plates. Leydig cells cultured on glass coverslips coated with ECM proteins for 24 hr exhibited elongated shapes with long cell processes (spreading), while cells cultured on uncoated plates showed few cell processes. A significant decrease in testosterone production was observed when basal and hCG-stimulated Leydig cells were cultured for 3 or 24 hr on plates coated with type IV collagen (12 and 24 microg/cm(2)) compared to uncoated plates. A significant though a slighter decrease in testosterone production was also observed in cells cultured on plates coated with fibronectin (12 and 24 microg/cm(2)), compared to uncoated plates. Laminin-1 did not modify testosterone production under basal or hCG stimulated conditions. These results suggest that ECM proteins are able to modulate Leydig cell steroidogenesis, in vitro.

Animals↗
PubMed1999

Extracellular matrix-integrin interactions in osteoblast function and tissue remodeling.

Previous work with cultured primary cells, from our group and from other laboratories, has shown that signals from extracellular matrix, transduced by integrins, play critical roles in regulating gene expression, tissue-specific differentiation, and survival of primary osteoblasts and fibroblasts. This summary will focus on our most recent work, dealing with the role of cell-extracellular matrix interactions and focal adhesion kinase in regulating cell survival in osteoblasts and fibroblasts, and the role of beta1 integrins in tissue organization and remodeling in bone.

Bone Remodeling↗
PubMed2002

Steroids modulate the expression of alpha4 integrin in mouse blastocysts and uterus during implantation.

Blastocyst implantation and successful establishment of pregnancy require delicate interactions between the embryo and the maternal uterine milieu, which are controlled at the embryo-maternal interface by the coordinated interplay of a variety of growth factors, cytokines, hormones, and cell adhesion molecules expressed by both the decidualized endometrium and the trophoblast cells. Proper implantation of the embryo is solely dependent on the initial endometrial receptivity and the preparation of the blastocyst to glue itself to the uterine wall. Both these events are considered to be mediated by cell adhesion molecules and integrins expressed by the blastocyst as well by as the maternal endometrium. Integrin expression by the blastocyst and the uterus is a dynamic process. However, reports on the expression and the hormonal modulation of integrins and their role in blastocyst activation and uterine receptivity during implantation are meager. The present study investigates the expression and hormonal regulation of alpha4beta1 integrin by steroid hormones in the blastocyst and the receptive uterus using an in vivo, delayed-implantation mouse model system. The dormant and activated blastocysts as well as the uteri were recovered from ovariectomized mice after progesterone-alone and progesterone-plus-estrogen therapy, respectively. Immunolocalization of protein expression of alpha4 and beta1 integrin subunits indicate that steroids modulate the expression of alpha4beta1 integrin receptor in the mouse blastocyst as well as the uterus and that a differential expression is observed with exposure to progesterone and estrogen. Intrauterine blocking of alpha4 integrin by specific antibody resulted in implantation failure in normal as well as in delayed-implantation mice. Based on our data, we propose here, to our knowledge for the first time, that alpha4beta1 integrin, which is responsible for binding to fibronectin and vascular cell adhesion molecule-1, is induced by estradiol and is down-regulated by progesterone in mice during implantation. Furthermore, the results also indicate the direct role of alpha4 integrin in the process of implantation.

Animals↗
PubMed2003

Complementary roles of glycoprotein VI and alpha2beta1 integrin in collagen-induced thrombus formation in flowing whole blood ex vivo.

Platelets interact vigorously with subendothelial collagens that are exposed by injury or pathological damage of a vessel wall. The collagen-bound platelets trap other platelets to form aggregates, and they expose phosphatidylserine (PS) required for coagulation. Both processes are implicated in the formation of vaso-occlusive thrombi. We previously demonstrated that the immunoglobulin receptor glycoprotein VI (GPVI), but not integrin alpha2beta1, is essential in priming platelet-collagen interaction and subsequent aggregation. Here, we report that these receptors have yet a complementary function in ex vivo thrombus formation during perfusion of whole blood over collagen. With mice deficient in GPVI or blocking antibodies, we found that GPVI was indispensable for collagen-dependent Ca2+ mobilization, exposure of PS, and aggregation of platelets. Deficiency of integrin beta1 reduces the GPVI-evoked responses but still allows the formation of loose platelet aggregates. By using mice deficient in G(alpha)q or specific thromboxane A2 and ADP antagonists, we show that these autocrine agents mediated aggregation but not collagen-induced Ca2+ mobilization or PS exposure. Collectively, these data indicate that integrin alpha2beta1 facilitates the central function of GPVI in the platelet activation processes that lead to thrombus formation, whereas the autocrine thromboxane A2 and ADP serve mainly to trigger aggregate formation.

Adenosine Diphosphate↗
PubMed2000

Integrin and dystrophin associated adhesion protein complexes during regeneration of shearing-type muscle injury.

In shearing injury both the myofibres and connective tissue framework are breached and the muscle tendon continuity is disrupted. During regeneration the firm myofibre to extracellular matrix (ECM) adhesion must be re-established. We have analysed the expression of selected molecules implementing this adhesion in regenerating myofibres 2-56 days after transection of rat soleus muscle using quantitative immunohistochemistry and Northern blotting. Beta1 integrin mRNA level and alpha7 integrin and vinculin immunoreactivities were transiently increased in both the intact and regenerating parts of the transected myofibres by day 5-7 with normalization by day 10-14. After day 14, alpha7 integrin and vinculin accumulated at the tips of the regenerating myofibres, indicating formation of new mini-myotendinous junctions (mMTJ). Immunoreactivities for dystrophin and associated proteins as well as merosin appeared in regenerating myotubes by day 3-4 reaching control levels by day 56. Our results suggest that integrin and dystrophin associated molecules are complementary in myofibre-ECM adhesion. During regeneration, ruptured myofibres temporarily reinforce their integrin mediated lateral adhesion until mMTJs are formed. Thereby the load on the newly formed scar and the risk of rerupture are reduced. Dystrophin associated molecules appear later and replace integrin on the lateral aspects, while both complexes are abundant at the mMTJs. These molecular events correspond to our previous results on tensile strength.

Animals↗
PubMed1996

Successful treatment of chronic leg ulcers with epidermal equivalents generated from cultured autologous outer root sheath cells.

The outer root sheath cells of hair follicles can substitute for interfollicular epidermal keratinocytes, as during healing of skin wounds when these cells migrate onto the denuded area and contribute to epidermal regeneration. Using improved culture techniques, we generated epidermal equivalents from cultured outer root sheath cells of patients suffering from recalcitrant chronic leg ulcers, primarily of vascular origin. In such epidermal equivalents, tissue organization as well as immunolocalization of epidermal differentiation products (keratin 10, involucrin, filaggrin) and integrins were indistinguishable from normal epidermis. As determined by the number of bromodeoxyuridine-incorporating cells, the basal layer contained a large compartment of proliferative cells irrespective of donor age. FACS analysis of the outer root sheath cells, used to prepare the epidermal equivalents, disclosed a fraction of small cells with enhanced expression of beta1-integrin, a potential stem cell marker. in contrast to acute wounds, a major definitive take of grafted cultured autologous keratinocytes has not been convincingly demonstrated in chronic wounds. In a pilot study, grafting of epidermal equivalents generated in vitro from autologous outer root sheath cells on 11 ulcers in five patients resulted in a definitive take rate of about 80%, with subsequent complete healing within 2 to 3 wk of five out of seven ulcers grafted with densely arranged cultures. This improvement in the treatment of chronic leg ulcers with cultured autologous keratinocytes probably depends on the large compartment of proliferative cells as well as on a well-developed horny layer which prevents disintegration of the grafts. Practical advantages of the new technique are its noninvasiveness, the lack of need for surgical facilities or anesthesia, and a short immobilization period after grafting.

Aged↗
PubMed2001

Osteopontin and its receptor alphavbeta(3) integrin are coexpressed in the human endometrium during the menstrual cycle but regulated differentially.

Osteopontin is an arginine-glycine-aspartic acid-containing acidic glycoprotein component of the extracellular matrix that is postulated to bind to integrin receptors at the cell surface to mediate cellular adhesion and migration during embryo implantation. The primary aim of this study was to examine the uterine expression of osteopontin throughout the menstrual cycle in normal fertile controls sampled prospectively based on urinary LH surge detection. Expression of osteopontin was documented using Northern blot analysis, in situ hybridization, and immunohistochemistry. Furthermore, the temporal pattern of osteopontin expression was compared with that of its receptor, the alphavbeta3 integrin. Using Ishikawa cells, a well differentiated endometrial adenocarcinoma cell line, the in vitro regulation of osteopontin and its receptor alphavbeta3 integrin was studied. By Northern blot analysis, osteopontin mRNA appears during the early secretory phase, with maximal expression occurring in mid to late secretory-phase endometrium. The in situ hybridization analyses showed that osteopontin mRNA specifically localized in epithelial cells within the endometrium. Immunostaining of osteopontin was detected in the glandular secretions and on the apical portions of surface (luminal) epithelium. The patterns of expression of osteopontin by Northern blotting, in situ hybridization, and immunohistochemistry are remarkably similar to the pattern for the alphavbeta3 integrin. Despite these similarities in distribution, in vitro studies demonstrate that osteopontin and beta3 integrin subunit expression are differentially regulated. The expression of osteopontin was primarily induced in response to progesterone, whereas the beta3 integrin subunit was up-regulated by epidermal growth factor or heparin-binding epidermal growth factor. The differential regulation of these two endometrial proteins suggests the existence of two separate pathways regulating epithelial gene expression in human endometrium during the window of implantation. In adhesion assays using Ishikawa cells, alphavbeta3 but not alphavbeta5 or beta1 integrins appear to be the primary receptors for osteopontin. These findings may better define the factors that favor the development of a receptive endometrium.

Adult↗
PubMed1999

The juxtamembrane domain of cadherin regulates integrin-mediated adhesion and neurite outgrowth.

Axons are guided along their trajectories during development by many different systems of adhesion, attraction, and repulsion. Thus, many distinct, and potentially competing, receptor systems respond to environmental cues, and the information must be coordinated inside the growth cone to ensure that extension follows the appropriate path. In this brief review we bring together two studies, each of which has defined different aspects of a pathway through which N-cadherin regulates beta1-integrin function allowing for coordinated responses to environmental cues during neurite extension. First we review progress in defining the binding to cells and the subsequent effects on adhesion and neurite outgrowth of the chondroitin sulfate proteoglycan, neurocan. Neurocan binds to a cell surface glycosyltransferase associated with N-cadherin (but not integrin), initiating a signal which results in loss of cadherin and integrin-function-suggesting that these two adhesion receptor systems engage in cross-talk, allowing coordinate regulation. Second, we review the use of "Trojan" peptides, peptides which mimic specific sequences in the cytoplasmic domain of N-cadherin attached to a cell permeation sequence, to reveal protein-protein interactions critical to cadherin-integrin cross-talk. One peptide mimicking a 20 amino acid sequence in the juxtamembrane region of N-cadherin has the same effect as neurocan, blocking both cadherin- and integrin-mediated adhesion and neurite outgrowth. Both neurocan and the peptide cause the release of the non-receptor tyrosine kinase Fer from the cadherin complex and its binding to the integrin complex. These data define an epigenetic pathway through which environmental cues are capable of coordinately regulating the activity of two developmentally important adhesion systems.

Animals↗
PubMed1999

HGF induces FAK activation and integrin-mediated adhesion in MTLn3 breast carcinoma cells.

Expression of hepatocyte growth factor (HGF) and its tyrosine kinase receptor, c-Met, is positively correlated with breast carcinoma progression. We found that in invasive and metastatic MTLn3 breast carcinoma cells, HGF stimulated both initial adhesion to and motility on the extracellular matrix (ECM) ligands laminin 1, type I collagen, and fibronectin. Next, analysis with function-perturbing antibodies showed that adhesion to the different ECM proteins was mediated through specific beta1 integrins. In MTLn3 cells, HGF induced rapid tyrosine phosphorylation and activation of both c-Met and focal adhesion kinase (FAK). Cell anchorage and adhesion to the ECM substrates was required for HGF-induced FAK activation, since HGF failed to trigger tyrosine phosphorylation of FAK in suspended cells. Our results provide evidence that the 2 signaling pathways, integrin/ECM and c-Met/HGF, cooperate synergistically to induce FAK activation in an adhesion-dependent manner, leading to enhanced cell adhesion and motility. Moreover, we found that a FRNK (the FAK-related non-kinase)-like molecule is expressed in MTLn3 cells. Since FRNK acts as a competitive inhibitor of FAK function, our results suggest that a FRNK-like protein could facilitate disassembly of focal adhesions and likely be responsible for the HGF-induced scattering and motility of MTLn3 cells.

Animals↗
PubMed2002

Neonatal infection with a milk-borne virus is independent of beta7 integrin- and L-selectin-expressing lymphocytes.

Mouse mammary tumor virus (MMTV) is acquired by neonates through milk and first infects lymphocytes in Peyer's patches. We show here that newborn mice lacking beta7 integrin or L-selectin were infected with MMTV at wild-type levels in both their lymphoid and mammary tissues. Superantigen-mediated activation and cognate T cell deletion were also unimpaired in both types of null mice. A large proportion of neonatal Peyer's patch lymphocytes in wild-type mice were beta7 and beta1 integrin low and both populations increased in response to MMTV infection. These results suggest that adhesion molecules other than beta7 integrin or L-selectin play a role in lymphocyte homing in the gut, peripheral lymph nodes and mammary gland in response to MMTV infection.

Animals↗
PubMed1997

Activation of phosphoinositide 3-OH kinase by the alpha6beta4 integrin promotes carcinoma invasion.

We demonstrate that the alpha6beta4 integrin promotes carcinoma invasion through a preferential and localized targeting of phosphoinositide-3 OH kinase (PI3K) activity. Stable expression of alpha6beta4 increased carcinoma invasion in a PI3K-dependent manner, and transient expression of a constitutively active PI3K increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more PI3K activity than ligation of beta1 integrins, establishing specificity among integrins for PI3K activation. Alpha6beta4-regulated PI3K activity was required for the formation of lamellae, dynamic sites of motility, in carcinoma cells. The small G protein Rac is required downstream of PI3K for invasion. These studies define a mechanism by which the alpha6beta4 integrin promotes carcinoma invasion and invoke a novel function for PI3K signaling.

Androstadienes↗
PubMed2003

Expression and biological role of laminin-1.

Of the approximately 15 laminin trimers described in mammals, laminin-1 expression seems to be largely limited to epithelial basement membranes. It appears early during epithelial morphogenesis in most tissues of the embryo, and remains present as a major epithelial laminin in some adult tissues. Previous organ culture studies with embryonic tissues have suggested that laminin-1 is important for epithelial development. Recent data using genetically manipulated embryonic stem (ES) cells grown as embryoid bodies provide strong support for the view of a specific role of laminin-1 in epithelial morphogenesis. One common consequence of genetic ablation of FGF signaling, beta1-integrin or laminin gamma1 chain expression in ES cells is the absence of laminin-1, which correlates with failure of BM assembly and epiblast differentiation. Partial but distinct rescue of epiblast differentiation has been achieved in all three mutants by exogenously added laminin-1. Laminin-1 contains several biologically active modules, but several are found in beta1 or gamma1 chains shared by at least 11 laminins. However, the carboxytermini of the alpha chains contain five laminin globular (LG) modules, distinct for each alpha chain. There is increasing evidence for a particular role of alpha1LG4 binding to its receptors for epithelial tubulogenesis. The biological roles of this and other domains of laminin-1 are currently being explored by genetic means. The pathways controlling laminin-1 synthesis have remained largely unknown, but recent advances raise the possibility that laminin-1 and collagen IV synthesis can be regulated by pro-survival kinases of the protein kinase B/Akt family.

Animals↗
PubMed2002

Specific SHP-2 partitioning in raft domains triggers integrin-mediated signaling via Rho activation.

Cell signaling does not occur randomly over the cell surface, but is integrated within cholesterol-enriched membrane domains, termed rafts. By targeting SHP-2 to raft domains or to a non-raft plasma membrane fraction, we studied the functional role of rafts in signaling. Serum-depleted, nonattached cells expressing the raft SHP-2 form, but not non-raft SHP-2, display signaling events resembling those observed after fibronectin attachment, such as beta1 integrin clustering, 397Y-FAK phosphorylation, and ERK activation, and also increases Rho-GTP levels. Expression of the dominant negative N19Rho abrogates raft-SHP-2-induced signaling, suggesting that Rho activation is a downstream event in SHP-2 signaling. Expression of a catalytic inactive SHP-2 mutant abrogates the adhesion-induced feedback inhibition of Rho activity, suggesting that SHP-2 contributes to adhesion-induced suppression of Rho activity. Because raft recruitment of SHP-2 occurs physiologically after cell attachment, these results provide a mechanism by which SHP-2 may influence cell adhesion and migration by spatially regulating Rho activity.

Blotting, Western↗
PubMed2005

alpha8beta1 Integrin expression in the rat carotid artery: involvement in smooth muscle cell migration and neointima formation.

OBJECTIVE: Migration of vascular smooth muscle cells (VSMCs) from the tunica media to the intima is a key event in neointima formation after coronary artery angioplasty. The central dogma in VSMC migration is cell modulation from the contractile to the noncontractile phenotype. Increased alpha8beta1 integrin expression, observed in situations where the majority of cells are in the contractile phenotype, led us to hypothesize that a decrease of alpha8beta1 integrin may play an important role in the migratory state of VSMCs. METHODS AND RESULTS: To test this hypothesis, neointima formation was induced in the left common carotid artery of adult male Sprague-Dawley rats by balloon dilatation. Immunohistochemical and Western blotting analysis showed reduced expression for up to 4 weeks of both the alpha8 and beta1 integrin subunits as well as smooth muscle alpha-actin in the tunica media following balloon injury. Moreover, ex vivo culture of carotid VSMCs revealed diminished alpha8 integrin expression in the platelet-derived growth-factor-dependent migratory state with an increase in the angiotensin-II-induced contractile state. To ascertain the functional role of alpha8 integrin in VSMC migration and proliferation, alpha8 gene expression was reduced by nearly 70% by short interference RNA (siRNA). Decreased alpha8 expression resulted in a significant increase of carotid VSMC migration but not of proliferation. CONCLUSIONS: Our results are consistent with those of other studies demonstrating that alpha8 integrin could be used as an appropriate differentiation marker. In addition, depressed alpha8 integrin expression (after vascular injury or siRNA knockdown) was correlated with heightened cell migratory activity, demonstrating its potential role in neointima formation.

Angioplasty, Balloon↗
PubMed1998

Integrin beta cytoplasmic domains differentially bind to cytoskeletal proteins.

Integrin cytoplasmic domains connect these receptors to the cytoskeleton. Furthermore, integrin-cytoskeletal interactions involve ligand binding (occupancy) to the integrin extracellular domain and clustering of the integrin. To construct mimics of the cytoplasmic face of an occupied and clustered integrin, we fused the cytoplasmic domains of integrin beta subunits to an N-terminal sequence containing four heptad repeat sequences. The heptad repeats form coiled coil dimers in which the cytoplasmic domains are parallel dimerized and held in an appropriate vertical stagger. In these mimics we found 1) that both conformation and protein binding properties are altered by insertion of Gly spacers C-terminal to the heptad repeat sequences; 2) that the cytoskeletal proteins talin and filamin are among the polypeptides that bind to the integrin beta1A tail. Filamin, but not talin binding, is enhanced by the insertion of Gly spacers; 3) binding of both cytoskeletal proteins to beta1A is direct and specific, since it occurs with purified talin and filamin and is inhibited in a point mutant (beta1A(Y788A)) or in splice variants (beta1B, beta1C) known to disrupt cytoskeletal associations of beta1 integrins; 4) that the muscle-specific splice variant, beta1D, binds talin more tightly than beta1A and is therefore predicted to form more stable cytoskeletal associations; and 5) that the beta7 cytoplasmic domain binds filamin better than beta1A. The structural specificity of these associations suggests that these mimics offer a useful approach for the analysis of the interactions and structure of the integrin cytoplasmic face.

Amino Acid Sequence↗
PubMed2004

Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of beta2 integrin gene expression.

Inflammatory responses are associated with significant changes in tissue metabolism. In particular, metabolic shifts during inflammation can result in significant tissue hypoxia, with resultant induction of hypoxia-responsive genes. Given this association, we hypothesized that leukocyte functional responses are influenced by hypoxia. Initial experiments revealed that exposure of the promonocytic cell line U937 to hypoxia resulted in increased adhesion to activated endothelia. Such increases were transcription-dependent and were blocked by antibodies directed against beta2, but not beta1, integrins. Analysis of beta2 integrin mRNA and protein in U937 cells revealed a 5- to 6-fold increase with hypoxia. Extension of this analysis to hypoxic human whole blood revealed prominent induction of beta2 integrin mRNA and protein ex vivo. Furthermore, murine beta2 integrin mRNA was found to be significantly induced during hypoxia in vivo. Subsequent studies identified a binding site for hypoxia-inducible factor 1 (HIF-1) in the CD18 gene. This gene encodes the subunit common to all four known types of beta2 integrin heterodimer. HIF-1 binding was demonstrated in vivo, and mutational analysis of the HIF-1 site within the CD18 promoter resulted in a loss of hypoxia inducibility. Taken together, these results demonstrate that hypoxia induces leukocyte beta2 integrin expression and function by transcriptional mechanisms dependent upon HIF-1.

Base Sequence↗
PubMed2000

Type VIII collagen stimulates smooth muscle cell migration and matrix metalloproteinase synthesis after arterial injury.

Type VIII collagen is a matrix protein expressed in a number of tissues undergoing active remodeling, including injured arteries during neointimal formation and in human atherosclerotic plaques; however, very little is known about its function. We have investigated whether the type VIII collagen stimulates smooth muscle cell (SMC) migration and invasion by binding to integrin receptors and up-regulating matrix metalloproteinase (MMP) production. SMCs attached to plates coated with type VIII collagen in a dose-dependent manner, with maximal attachment occurring with coating solutions containing 25 microgram/ml collagen. Type VIII collagen at 100 microgram/ml stimulated an 83-fold increase in the migration of SMCs in a chemotaxis chamber. Antibodies against beta1 integrin receptors prevented attachment and migration of SMCs. Antibodies against alpha1 or alpha2 integrins reduced attachment of SMCs to type VIII collagen by 29% and 77%, respectively. We found that SMCs grown from the rat neointima, but not medial SMCs, increased their production of MMP-2 and -9 on adherence to type VIII collagen. This suggests that there is an important difference in phenotype between intimal and medial SMCs and that intimal SMCs have distinct matrix-dependent signaling mechanisms. Our findings suggest that type VIII collagen deposited in vascular lesions functions to promote SMC attachment and chemotaxis, and signals through integrin receptors to stimulate MMP synthesis, all of which are important mechanisms used in cell migration and invasion.

Animals↗