A Collagen/Laminin Receptor on Others MARIANO J

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A Collagen/Laminin Receptor on Others MARIANO J Proc. Nati. Acad. Sci. USA Vol. 86, pp. 9906-9910, December 1989 Cell Biology The human integrin VLA-2 is a collagen receptor on some cells and a collagen/laminin receptor on others MARIANO J. ELICES AND MARTIN E. HEMLER* Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 Communicated by Elizabeth D. Hay, September 5, 1989 ABSTRACT The integrin heterodimer VLA-2, previously platelet nor fibroblast VLA-2 appears to interact with lami- known as a collagen receptor, is now shown also to be a laminin nin. receptor. Adhesion of the human melanoma cell line LOX to laminin was inhibited by anti-VLA a2 antibodies. Because VLA-2-mediated LOX cell attachment to laminin was not METHODS inhibited by digestion with collagenase, collagen contamination Antibodies and Cells. The monoclonal antibodies (mAbs) oflaminin was not a factor. In addition, VLA-2 from LOX cells A-lA5 (anti-f81), TS2/7 (anti-a'), 12F1 (anti-a2), J143 (anti- bound to immobilized laminin, and binding was disrupted by a3), and the control mAbs P3 and J-2A2 were obtained as EDTA but not by Arg-Gly-Asp (RGD) peptides. VLA-3 also described (22). The mAbs PlH5 and PlB5 that recognize the bound to lammnin-Sepharose, although less avidly than VLA-2. VLA a2 and a3 subunits, respectively (19, 20), were from E. Thus, at least four separate members of the integrin .,8 Wayner (University of Washington, Seattle). Anti-VLA-2 subfamily serve as laminin receptors-i.e., VLA-2 and VLA-3 mAbs 5E8 (23) and Gil4 (24) were from R. Bankert (Roswell (this study) together with VLA-1 and VLA-6 (other reports). Park Memorial Institute, Buffalo, NY) and S. Santoso (Gies- Whereas LOX and other cell lines used VLA-2 as both a sen, F.R.G.), respectively. The mAbs BlE5 and BlEll laminin and collagen receptor, fibroblast VLA-2 mediated recognize epitopes on VLA aS and f1, respectively, and were collagen but not laminin binding. Likewise, VLA-2 from provided by C. Damsky (University of California, San Fran- platelets did not interact with laminin. Despite this functional cisco). GoH3, a mAb specific for VLA a6 (25), was obtained discordancy, VLA-2 from laminin-binding and nonbinding from A. Sonnenberg (The Netherlands Cancer Institute, sources was indistinguishable by all immunochemical and Amsterdam). Finally, a rabbit heteroantiserum to a synthetic biochemical criteria examined. Thus, functional differences in peptide from the COOH-terminal intracytoplasmic portion of VLA-2 may be due to cell type-specific modulation. VLA a2 (26) was prepared in this laboratory. The human melanoma cell line LOX was obtained from Laminin, a major constituent of basement membranes, pro- Lan Bo Chen (Dana-Farber Cancer Institute). All the cell motes adhesion, growth, migration, and differentiation of lines described in Table 1 were grown in RPMI 1640 medium cells (1). The laminin glycoprotein (Mr 900,000) consists of containing 10o fetal bovine serum. three subunits arranged in the shape of a cross with one long Matrix Proteins. Laminin from the Engelbreth-Holm- and three short arms (1). Distinct functions of laminin, such Swarm (EHS) murine tumor (27) was a gift from H. Kleinman as promotion ofneurite outgrowth, interaction with basement (National Institute of Dental Research, Bethesda, MD). membrane components, and attachment and spreading of Fibronectin was purified from human plasma (28), and col- cells, each reside within separate structural domains (1). In lagens type I and IV were purchased from Telios Pharma- particular, cell adhesion appears to be mediated by at least ceuticals (La Jolla, CA). three different regions in laminin (2-5), and a peptide derived Cell Attachment and mAb Inhibition Assays. To assess cell from one of the cell-binding sites has been shown to inhibit attachment to extracellular matrix proteins, cells were incu- bated with 51Cr (0.5 ,Ci; 1 Ci = 37 GBq) overnight, washed experimental metastasis (6). three times, and resuspended in RPMI 1640 supplemented Thus far, specific cell-adhesion receptors for laminin in- with 0.5% fetal bovine serum and 0.1 mM MnC12. Then 1.5 clude a 68-kDa protein (7-9), as well as other surface mole- x 103 cells per well were plated in triplicate for 20-30 min at cules that belong to the integrin family. Integrins are a group 37°C on 96-well microtiter dishes (0.8-cm diameter per well) of af3 heterodimers involved in cell-cell and cell-extracellu- that were previously incubated with laminin, collagen, or lar matrix interactions, some of which occur via recognition fibronectin (1 ,g/well). After unbound cells were aspirated, ofan Arg-Gly-Asp (RGD) tripeptide sequence present in their and the plates were washed twice with RPMI 1640, 51Cr ligands (10, 11). Members ofthe integrin family implicated as present in 0.1% SDS cell lysates was measured by using a y laminin receptors include a rat cell complex that resembles counter. For mAb inhibition experiments, labeled cells were VLA-3 (12), human VLA-6 from platelets (13), and a rat cell incubated with mAbs for 30 min at 4°C, washed, and plated complex that may be the homolog of human VLA-1 (14). on matrix ligand as described above. Specific attachment was VLA-2, another member of the integrin ,1 subfamily, has calculated by subtracting the radioactivity bound to bovine been shown to act as a cell-surface receptor for collagen in serum albumin-coated controls. platelets (15-18), fibroblasts (19, 20), and melanoma cells Laminin-Sepharose Affinity Chromatography. Human (21). However, in the platelet system VLA-2 was clearly LOX melanoma cells were detached from tissue culture unable to mediate cell binding to laminin (13, 18). In the flasks with 0.03% EDTA in phosphate-buffered saline (PBS), present report, a role for VLA-2 as a laminin receptor in washed twice with PBS, and iodinated with 2 ,uCi of Na1251 human LOX melanoma cells, as well as other cell lines, is (DuPont/NEN) and lactoperoxidase at 0.2 mg/ml (Sigma) for unequivocally demonstrated, despite finding that neither 2-5 x 107 cells. lodinated cells were lysed with 0.1 M octyl The publication costs of this article were defrayed in part by page charge Abbreviations: mAb, monoclonal antibody; PBS, phosphate- payment. This article must therefore be hereby marked "advertisement" buffered saline. in accordance with 18 U.S.C. §1734 solely to indicate this fact. *To whom reprint requests should be addressed. 9906 Downloaded by guest on September 24, 2021 Cell Biology: Elices and Hernler Proc. Natl. Acad. Sci. USA 86 (1989) 9907 glucoside (Sigma) and 0.1 M octyl thioglucoside (Calbio- laminin-coated plastic surfaces, with half-maximal binding at chem) in PBS containing 0.1 mM MnCI2, aprotinin at 10 0.5 ,ug oflaminin per well (data not shown). To investigate the ,ug/ml, 10 juM leupeptin, and 1 mM phenylmethylsulfonyl contribution of VLA heterodimers to melanoma-cell adhe- fluoride for 4 hr at 40C. Detergent lysates were clarified by sion on laminin, a panel of mAbs was tested for inhibition of centrifugation at 12,000 x g, supplemented with bovine cell binding (Fig. 1A). Cell attachment to laminin could be serum albumin (0.5 mg/ml), and loaded onto 2 ml oflaminin- completely abolished by incubation with the mAb BlEll Sepharose columns (3.5 mg of laminin per ml of packed (anti-VLA p1), thus indicating that f1 integrins had a major beads) preequilibrated with 25 mM each of octyl glucoside role in LOX cell adhesion to laminin. Ofthe mAbs against the and octyl thioglucoside in the same buffer as above (buffer VLA proteins expressed on the surface ofLOX cells (VLA-1, A). After equilibration for 2 hr, columns were washed with -2, -3, -5, and -6) only anti-VLA a2 mAb 5E8 (Fig. 1A) and buffer A until eluted radioactivity decreased to background P1H5 (data not shown) substantially inhibited melanoma-cell levels (-20 column volumes). Stepwise elution was con- adhesion to laminin. In contrast, neither mAbs PlB5 (anti- ducted with 0.5 M NaCi, 10 mM EDTA, and 4 M urea, each VLA a 3) and BlE5 (anti-VLA a5) (Fig. 1A) nor TS2/7 in buffer A. Fractions (0.8 ml each) were collected and (anti-VLA a') and GoH3 (anti-VLA a 6) were inhibitory (data analyzed for radioactivity with a y counter. Immunoprecip- not shown). The prototype anti-a2 mAb 12F1 (31) did not itation of labeled proteins was done as described (22). block cell binding to either laminin or collagen type I, NH2-Terminal Sequencing of a2 Subunit. VLA-2 was pu- although material immunoreactive with either 5E8 or 12F1 rified from LOX (1 x 109 cells) by using lectin affinity was reciprocally precleared by incubation with the other chromatography, followed by Gil4-Sepharose chromatogra- mAb (Fig. 1B). Thus, 12F1 and 5E8 both bound to VLA-2 but phy with described methods (29). The mAb Gil4 bound might differ in epitope recognition. Upon titration with in- quantitatively to all VLA-2, whether from laminin binding or creasing concentrations of mAb 5E8 (Fig. 1C), a maximal nonbinding cells. After purification, VLA-2 subunits were inhibition of 70% was obtained when laminin was saturating separated by SDS/PAGE and then transferred to polyvinyl- for cell adhesion. At lower levels oflaminin, LOX cells bound idene difluoride membrane (Immobilon, Millipore), as de- to laminin-coated plates with less avidity, and thus inhibition scribed (30). The a2 polypeptide chain was identified by by mAb 5E8 approached 100% (data not shown). staining with Coomassie blue, cut from the membrane, and Comparison of Matrix Adhesion for LOX and Other Cells. the NH2-terminal amino acid sequence was determined at the To determine whether various human cell lines may use Harvard Microsequencing Facility, Cambridge, MA.
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