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Cell Biology International (2006) 30, 784792 (Printed in Great Britain)
Contribution of α2β1, α3β1, α6β4 integrins and 67
Olga A. Cherepanova*1, Natalia Kalmykova, Yury P. Petrov, Miralda Blinova and George Pinaev
Department of Cell Culture, Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
Laminin-2/4 is the major laminin isoform of normal muscle and nerve tissues and plays an important role in tumor invasion and metastasis. Despite the fact that laminin-2/4 has been found in the skin basement membrane, insufficient evidence is available on the effect of laminin-2/4 on the behavior of both normal and transformed skin cells. A comparison of the contribution of α2β1, α3β1, α6β4 integrins and 67
Keywords: Laminin-2/4, Integrins, 67
1Contract grant sponsor: Russian Foundation for Basic Research; Contract grant number: 03-04-48251.
*Corresponding author. Cardiovascular Research Center, 415 Lane Road, MR5 RM 1328, Charlottesville, VA 22908, USA. Tel.: +1 434 924 5993; fax: +1 434 982 0055.
The mechanisms of cell regulation are the main problems of cell biology. In tissues of living organisms, this regulation is realized by interaction of ambient bioactive molecules with cell receptors. The extracellular matrix (ECM) glycoproteins, which interact with cell adhesion receptor integrins and regulate proliferation, differentiation and motility of cells, are types of bioactive molecules (Adams and Watt, 1993; Roskelly et al., 1995).
The interaction of cells with ECM is a complicated process, consisting of cell attachment, spreading, focal contacts and stress fiber formation followed by cell migration or cell stabilization. ECM glycoproteins are large multidomain molecules and they interact with cell surface receptors by means of short amino acid sequences. The fibronectin sequence RGD mediates cell adhesion and cell spreading; collagen I and IV have both RGD and other sequences (Yamada and Kennedy, 1985; Raghow, 1994). The formation of complexes of ECM glycoproteins with cell receptors is accompanied by activation of signaling pathways and as a result of this the expression of specific genes occurs (Van der Flier and Sonnenberg, 2001; Hynes, 2002; DeMali et al., 2003). Little is known about the contribution of the sequences of ECM molecules and cell surface receptors at different stages of cell–matrix interactions.
The ECM glycoprotein laminin has the largest number of sequences for cell surface receptors (Nomizu et al., 1995; Yoshida et al., 1999). Laminins along with collagen IV and proteoglycans form the structure of basement membrane (BM), a network of specific ECM proximately touching cells (Engbring and Kleinman, 2003; Sasaki et al., 2004). Currently, at least 12 different isoforms of laminin in various tissues are known (Patarroyo et al., 2002). The most characterized isoform is laminin-1 from Engelberth-Holm-Swarm mouse sarcoma. It is composed of α1, β1 and γ1 chains bound by S-S links (Beck et al., 1990). Laminin-2/4 (α2β1/2γ1) from human placenta has 50% homology to laminin-1 amino acid sequence and equal domain composition (Vuolteenaho et al., 1994). The laminin α2 chain (laminin-2/4) was found in BM of skeletal muscle, heart muscle and Schwann cells (Leivo and Engvall, 1988; Ehrig et al., 1990). It has been shown that mutations in the laminin α2 chain result in muscular dystrophy (Wewer and Engvall, 1996; Cohn et al., 1998; Guo et al., 2003).
Although laminin-2/4 has been found in the skin (Sollberg et al., 1992; Sewry et al., 1996; Squarzoni et al., 1997), its specific interactions with skin cells are not as well characterized as those of laminin-1 and laminin-5. In addition, it has been reported that the expression of the α2 subunit of laminin correlates with increased cell adhesion and metastatic propensity (Jenq et al., 1994). Thus, laminin-2/4 can play an essential role in both normal skin morphogenesis and skin carcinogenesis. We have shown that laminin-2/4 is a better adhesion agent for human keratinocytes and epidermoid carcinoma A-431 cells than laminin-1 (Gorelik et al., 2001; Voronkina et al., 1999).
In this study, we applied a number of methods to compare the contribution of laminin receptors to different stages of the interaction of cells with laminin-2/4 (from attachment to motility). We used human epidermoid carcinoma cells, A-431, as a model, since a wealth of information about the receptors to laminin-1 is available.
2 Materials and methods
2.1 Cells and reagents
The transformed human epidermoid carcinoma cell line A-431 was obtained from the Russian Cell Culture Collection (Institute of Cytology RAS, St. Petersburg) and maintained in Dulbecco's modified Eagle's medium (DMEM) with 10% fetal calf serum.
Laminin isoforms were isolated from murine EHS-sarcoma (laminin-1) and human placenta (laminin-2/4) as previously described (Palm and Furcht, 1983, Gorelik et al., 2001). Proteins were stored at −70
To determine the contribution of α2β1, α3β1, α6β4 integrins and 67
2.2 Protein-coated latex bead assay
Latex beads D
2.3 Cell adhesion assay
Multiwell tissue culture plates (96-wells, Nunc) were coated with laminin-1 or laminin-2/4 (20
2.4 Cell motility assay
The cell motility assay was performed as described in Albrecht-Buehler (1977) with some modifications. Cover slips were treated with extracellular matrix proteins laminin-1 or laminin-2/4 (20
2.5 Cytoskeleton staining assay
Cytoskeleton staining assay was performed as described previously (Are et al., 2001). Glass cover slips, treated with Repell-Silane (Pharmacia Biotech, Sweden) were coated with laminin-1 or laminin-2/4 at 20
For visualization of the actin filament system, detached cells were plated on ligand-coated glass cover slips in CO
3.1 Integrins α2β1, α3β1, α6β4 participate in early stage of interaction of A-431 cells with laminin-2/4
A latex bead assay was proposed for the study of the early adhesion stage (attachment) (Gorelik et al., 2001). The incubation of human epidermoid carcinoma A-431 cells with protein-coated latex beads was performed on ice for 1
The comparison of laminin-1 and laminin-2/4-covered latex beads binding to human epidermoid carcinoma A-431 cells after 1
Previously it has been shown that the A-431 cell surface has α2β1, α3β1, α6β4 integrins and 67
The differences in the relative number of latex beads covered by laminin-2/4 attached to A-431 cells after incubation of cells with Abs to α2-integrins, α3-integrins, α2- and α3-integrins simultaneously, β1-integrins, β4-integrins and YIGSR peptide. The certain changes of the laminin-2/4-bead number were observed after treatment of cells with Abs to α2-integrins, α3-integrins, α2- and α3-integrins simultaneously, β1-integrins, β4-integrins, but not YIGSR peptide. The data represent the percentage of latex beads covered with laminin-2/4 relative to the control (untreated cells). Bars
3.2 Contribution of receptors to spreading of A-431 cells on laminin-2/4 differs from that to the attachment of the cells
The latex bead assay describes early interaction between receptors and laminin only. The classical quantitative adhesion assay for cell spreading on substrate was applied as the model characterizing cell receptor–laminin interactions in vivo, when the cells are polarized and attached to BM by their basal surface.
Previously, it has been shown that the adhesion of A-431 cells to laminin-2/4 substratum is more effective than the adhesion to laminin-1 (Voronkina et al., 1999). The results of the influence of the cell pretreatments with antibodies and YIGSR peptide on A-431 cells adhesion to laminin-2/4 substratum are summarized in Fig. 3. Although antibodies to α2- and α3-integrin subunits alone could not inhibit cell adhesion to laminin-2/4, the simultaneous treatment of the cells with these antibodies decreased adhesion approximately by a factor of two, indicating cooperative action of α2β1 and α3β1 integrins. Preincubation with antibodies to β4-integrin subunit alone resulted in a small increase in adhesion of A-431 cells to laminin-2/4, supporting the fact that α6β4 integrins are not essential for adhesion at this stage. In contrast, treatment of the cells with YIGSR peptide resulted in a significant decrease in adhesion of the cells to laminin-2/4. From these observations we concluded that the contribution of receptors is different at different stages of interaction of laminins with cells.
The alteration of A-431 cell adhesion to laminin-2/4-substratum after treatment of cells with Abs to α2-integrins, α3-integrins, α2- and α3-integrins simultaneously (a), β4-integrins and YIGSR peptide (b). Cell adhesion was measured as crystal violet staining intensity at 570
3.3 Effect of antibody treatment on the polarization of cells spread on the laminin-covered substrata
A cytoskeleton assay was suggested for the study of cell phenotypes in the late adhesion stage (spreading). A-431 cells did not demonstrate visible alterations in cytoskeleton patterns on substrata coated by laminin-1 or laminin-2/4 (Fig. 4) either before or after treatments with antibodies to β4-, β1-, α2- and α3-integrin subunits. In order to quantify these data, the notion of the criterion of polarization was introduced as follows. We separated five general groups of the cells after 1
Organization of actin cytoskeleton patterns in the A-431 cells spread on laminin-1 (a) and laminin-2/4 (b) substrata X 100. The cells were plated on cover slips (100
Five groups of A-431 cells after spreading on laminin-coated substrata. After incubation as described in the legend to Fig. 4, the spread cells were fixed and stained with rhodamin-phalloidin X 100. To quantify the spreading degree for different cells, each cell was represented as an ellipse (f). Five general groups of the cells were separated. Group 1 consists of unpolarized cells. The ratios of the lengths of the major and minor axes of an ellipse (h) were given as the characters of groups 2–5.
The criterion of polarization has allowed an estimate of the variations in the degree of polarization of the cells after treatment with different antibodies. Fig. 6 demonstrates the relative change of the criterion of polarization of A-431 cells after different treatments (ΔK). The criterion of polarization of untreated cells was taken as zero (the X-axis). The negative values of ΔK correspond to reduction of cell polarization after pretreatment with an antibody; the positive values correspond to increase of cell polarization. Since information about laminin-1 receptors on A-431 cells surface was available, laminin-1 action was used for comparison with laminin-2/4 action. After treatment of cells with antibodies to β1-integrin subunit alone and simultaneously with antibodies to α2- and α3-integrin subunits, the polarization of the cells on the laminin-1-coated substratum was almost the same. After treatment of cells with antibodies to β1-integrin the criterion of polarization of A-431 cells on laminin-2/4-coated substratum decreased, and it was constant after simultaneous treatment with antibodies to α2- and α3-integrin subunits, confirming the observation about cooperative action of α2β1 and α3β1 integrins in the adhesion assay. The antibodies to β4-integrin subunit had no effect on the criterion of polarization of A-431 cells on laminin-1-coated substratum (K
The differences in the criterion of polarization (ΔK) for A-431 cells on laminin-1 and laminin-2/4 substrata after cell treatment with Abs to α2-integrins, α3-integrins, α2- and α3-integrins simultaneously, β1-integrins, β4-integrins and YIGSR peptide. The ΔK of non-treated cells is taken as zero (the X-axis). Bars
Previously, co-regulation and physical association of the 67 LR and α6β4 integrin during A-431 cells interaction with laminin-1 were reported (Ardini et al., 1997). In order to check this possibility for laminin-2/4, preincubation with a combination of antibodies to β4-integrin subunit and YIGSR peptide was performed. There was an increase of K
3.4 Contribution of α2β1, α3β1, α6β4 integrins to the EGF-induced A-431 cell motility
To determine which integrin(s) are involved in the cell motility on laminin-2/4, we employed the modified phagokinetic assay as previously described (Albrecht-Buehler, 1977). We used latex beads (D
The micrograph of A-431 cells on laminin-2/4-covered substratum without motility (a) and the cells migrated on laminin-2/4-covered substratum in the presence of EGF (b) after 24
The preincubation of A-431 cells with antibodies to β4-integrin subunit caused a fivefold increase in motility in the absence of EGF. After simultaneous exposure of antibodies to β4-integrin subunit and EGF a significant additional increase in motility was observed. Antibodies to β1-integrin subunit alone had no effect on motility. After treatment of the cells with antibodies to β1-integrin subunit, EGF-induced motility was less than EGF-induced migration of untreated cells. These results suggest that β1-integrins and α6β4 integrins play opposite roles in A-431 cell motility on laminin-2/4.
Since β1-integrins are represented by both α2β1 and α3β1, we investigated the effect of antibodies to α2- and α3-integrin subunits on the A-431 cell motility on laminin-2/4 (Fig. 8). Antibodies to α2- and α3-integrin subunits had no influence on the motility of A-431 cells in the absence of EGF stimulation. Similarly, removing α3β1 from interaction had no effect on the A-431 cell EGF-induced motility. However, antibodies to the α2-integrin subunit almost completely blocked EGF-induced motility. These findings indicate that α2β1 integrin plays a determinative role in EGF-induced motility of A-431 cells on laminin-2/4-coated substratum.
The alteration of A-431 cell motility on laminin-2/4-coated substratum after cell treatment with Abs to β1-integrins, β4-integrins (a), α2-integrins and α3-integrins (b). The area of the motility tracks was measured and presented as the percentage of total cover slip area. Bar
Our attention was focused on the laminin-2/4 interaction with human epidermoid carcinoma A-431 cells (transformed keratinocytes). In this study, we compared the contribution of A-431 cell receptors, earlier described as receptors for laminin-1, to different stages of the interaction of A-431 cells with laminin-2/4. We proposed a number of methods for the investigation of different stages of cell–matrix interaction.
The α6β4 integrin possesses unique dual properties. On one hand, α6β4 is a fundamental component of stable adhesion complexes in the normal epithelium termed hemidesmosomes and links the EM with intermediate filaments (Borradori and Sonnenberg, 1999; Burgeson and Christiano, 1994). On the other hand, α6β4 induces migration of carcinoma cells through its ability to interact with the actin cytoskeleton (Rabinovitz and Mercurio, 1997; Rabinovitz et al., 1999). Thus, α6β4 integrin is an important receptor for malignant cell transformation. Our study demonstrates that the α6β4 integrins are involved in the primary interaction of A-431 cells with laminin-2/4, but their contribution to adhesion cell spreading on substratum is ambiguous, while the elimination of α6β4 from the interaction with laminin-2/4 resulted in only a small influence on the number of adhered cells. It has been previously established that α6β4 integrin does not participate in early steps of keratinocytes adhesion. Instead, it stabilizes the stable adhesion complexes that are formed in later stages of the adhesion process (Carter et al., 1990). However, α6β4 integrin may participate in early steps of adhesion when cells directly interact with laminin without needing to synthesize their own matrix (Karecla et al., 1994).
It should be noted that the hydrophobic surface of laminin-covered latex beads and the culture plates hydrophilic surface covered with laminins may differ. It was shown that the polarization of cells on laminin-2/4-coated substratum, but not on laminin-1-covered substratum, depends strongly on α6β4. Furthermore, the anti-α6β4 antibodies increase both the EGF-induced motility of A-431 cells and motility without EGF stimulation. Taken together, these data suggest that a determinate stage of α6β4-linked activation of signal pathways leading to A-431 cell motility is the earlier stage (attachment) of the interaction of cells with laminin-2/4.
In contrast, our data on the preincubation of A-431 cells with YIGSR peptide indicate that the 67 LR does not participate at an earlier interaction stage of A-431 cells with laminin-2/4. Recent studies described 67 LRs as the most numerous receptors on the A-431 cell surface (Ardini et al., 1997). Moreover, expression of 67 LR has been found to correlate with the metastatic potential of tumors (Sobel, 1993). Our experiments demonstrate that the elimination of 67 LR from the interaction of A-431 cells with laminin-2/4 leads to a decrease in cell polarization on laminin-2/4 and to an increased one on laminin-1. A number of studies have demonstrated the co-expression and correlation between the level of 67 LR and integrins with α6-subunits (α6β1 and α6β4) and their adhesion to laminin-1 (Ardini et al., 1997; Pellegrini et al., 1994; Romanov et al., 1994). Thus, the fact that YIGSR peptide did not have an influence on the attachment of A-431 cells to laminin-covered latex beads may be explained in the following way: 67 LR does not participate in the primary interaction of A-431 cells with laminins but it can participate in cell spreading on laminin-coated substrata which is compatible with our data obtained in the adhesion assay and cytoskeleton assay. Since both laminin isoforms have the YIGSR sequence, we speculated that the opposing action of the YIGSR peptide treatment on cell spreading (ΔK) for laminin-1 and laminin-2/4 could be due to the interference of α6β4 integrin and 67 LR. To check this possibility, the simultaneous action of anti-β4 antibodies and YIGSR peptide was studied. The average value (as the result of two individual treatments) must be obtained if the cooperation between α6β4 integrin and 67 LR does not occur. Thus, the mutual interaction between α6β4 and 67 LR was found for A-431 cell spreading on laminin-1, but not on laminin-2/4. It is possible that cooperative action for α6β4 and 67 LR is one of the causes of the different effects of laminin-1 and laminin-2/4 on the cell response.
We next examined the contribution of α2β1 and α3β1 integrins to different stages of the interaction of A-431 cells with laminin-2/4. We showed that both α2β1 and α3β1 integrins participate in the attachment of A-431 cells to laminin-2/4-coated latex beads. In contrast, we found no effect of the anti-α2- or anti-α3-antibody treatment if either of them is used alone. It was demonstrated that laminin-2/4 is not a ligand for α3β1 integrin (Eble et al., 1998; Nishiuchi et al., 2003). However, since a combination of α2β1 and α3β1 integrin-blocking antibodies has significantly decreased the cell adhesion, we suggested that the interplay between these receptors is probably involved at the A-431 cell interaction with laminin-2/4. In support of this suggestion, we found that α3β1 integrin alone did not affect cell polarization on laminin-2/4-coated substratum, but it mediated α2β1 integrin-dependent cell spreading.
The consistency of our observations with earlier findings about a role of α3β1 as a trans-dominant inhibitor of fibronectin and collagen IV integrin receptors in keratinocytes (Hodivala-Dilke et al., 1998) further strengthens the view that the interplay between α2β1 and α3β1 integrins takes place during A-431 cell interaction with laminin-2/4.
It was shown that α3β1 and α6β4 integrins are the receptors for keratinocyte adhesion and migration on laminin-5 (Shang et al., 2001; Gagnoux-Palacios et al., 2001). The α2β1 integrin was shown to be the basic collagen receptor as well as a receptor for laminin (Pfaff et al., 1994; Colognato et al., 1997). Furthermore, studies on the integrin expression revealed the presence of α2β1 integrin correlated with expression of the laminin-2 isoform in metastatic melanoma cells (Han et al., 1999). Our cell motility assay results showed that α2β1 integrin took direct place in the EGF-induced A-431 cell motility on laminin-2/4, while α6β4 integrin participates in the formation of stable cell–laminin-2/4 contacts, preventing cell migration. We also demonstrated that integrin α3β1 did not influence the A-431 cell motility on laminin-2/4-coated substrate. It is noteworthy that α2β1 integrin is colocolized with EGF receptors in A-431 cells (Yu et al., 2000). It is well known that the crosstalk between integrins and growth factor receptors is an important factor in the development of biochemical responses in different cells (Eliceiri, 2001). This evidence may explain the fact that certain integrins have definitive properties permanent for different cell types.
Overall, our conclusions can be summarized as follows: (1) the interaction of epidermoid carcinoma A-431 cells with laminin-2/4 is mediated by α2β1, α3β1, α6β4 integrins and 67 LR; (2) the interaction of α6β4 integrins with laminin-2/4 mediates a stable adhesion and prevents cell motility; (3) α2β1 participates in the EGF-induced A-431 cell motility on laminin-2/4. From the aforementioned it seems reasonable to suggest that (1) the α6β4 integrin ligation on the earlier stage of interaction determines the different character of interactions of 67 LR with laminin-1 and laminin-2/4 on spreading stage; (2) the cooperative action of α2β1 and α3β1 integrins affects the adhesion of A-431 cells on laminin-2/4. Furthermore, our results demonstrate that the contribution of the same type of receptors to various stages of interaction of cells with laminin can be different.
We thank Dr. E. Engvall for kindly providing antibodies to β4-integrin subunit and 4C7. We are grateful to Drs. Irina Kropacheva, Elena Kuzminykch, Olga Petoukhova and Lidia Turoverova, Irina Voronkina and Svyatoslav Tkachenko for helpful ideas and contributions to this work. This work was supported by a grant from the Russian Foundation for Basic Research No. 03-04-48251.
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Received 4 January 2006/4 May 2006; accepted 23 June 2006doi:10.1016/j.cellbi.2006.06.012