αvβ5 Integrin Sustains Growth of Human Pre-B Cells through an RGD-independent Interaction with a Basic Domain of the CD23 Protein

Abstract

CD23 is a type II transmembrane glycoprotein synthesized by hematopoietic cells that has biological activity in both membrane-bound and freely soluble forms, acting via a number of receptors, including integrins. We demonstrate here that soluble CD23 (sCD23) sustains growth of human B cell precursors via an RGD-independent interaction with the αvβ5 integrin. The integrin recognizes a tripeptide motif in a small disulfide-bonded loop at the N terminus of the lectin head region of CD23, centered around Arg172, Lys173, and Cys174 (RKC). This RKC motif is present in all forms of sCD23 with cytokine-like activity, and cytokine activity is independent of the lectin head, an “inverse RGD” motif, and the CD21 and IgE binding sites. RKC-containing peptides derived from this region of CD23 bind αvβ5 and are biologically active. The binding and activity of these peptides is unaffected by inclusion of a short peptide containing the classic RGD sequence recognized by integrins, and, in far-Western analyses, RKC-containing peptides bind to the β subunit of the αvβ5 integrin. The interaction between αvβ5 and sCD23 indicates that integrins deliver to cells important signals initiated by soluble ligands without the requirement for interactions with RGD motifs in their common ligands. This mode of integrin signaling may not be restricted to αvβ5. CD23 is a type II transmembrane glycoprotein synthesized by hematopoietic cells that has biological activity in both membrane-bound and freely soluble forms, acting via a number of receptors, including integrins. We demonstrate here that soluble CD23 (sCD23) sustains growth of human B cell precursors via an RGD-independent interaction with the αvβ5 integrin. The integrin recognizes a tripeptide motif in a small disulfide-bonded loop at the N terminus of the lectin head region of CD23, centered around Arg172, Lys173, and Cys174 (RKC). This RKC motif is present in all forms of sCD23 with cytokine-like activity, and cytokine activity is independent of the lectin head, an “inverse RGD” motif, and the CD21 and IgE binding sites. RKC-containing peptides derived from this region of CD23 bind αvβ5 and are biologically active. The binding and activity of these peptides is unaffected by inclusion of a short peptide containing the classic RGD sequence recognized by integrins, and, in far-Western analyses, RKC-containing peptides bind to the β subunit of the αvβ5 integrin. The interaction between αvβ5 and sCD23 indicates that integrins deliver to cells important signals initiated by soluble ligands without the requirement for interactions with RGD motifs in their common ligands. This mode of integrin signaling may not be restricted to αvβ5. CD23 is a 45-kDa type II transmembrane glycoprotein that functions as the low affinity receptor for IgE and negatively regulates IgE production by B lymphocytes (1Gould H.J. Sutton B.J. Beavil A.J. Beavil R.L. McCloskey N. Coker H.A. Fear D. Smurthwaite L. Annu. Rev. Immunol. 2003; 21: 579-628Crossref PubMed Scopus (539) Google Scholar, 2Bonnefoy J.-Y. Lecoanet-Henchoz S. Gauchat J.F. Graber P. Aubry J.P. Jeannin P. Plater-Zyberk C. Int. Rev. Immunol. 1997; 16: 113-128Crossref PubMed Scopus (68) Google Scholar, 3Delespesse G. Sarfati M. Wu C.Y. Fournier S. Letellier M. Immunol. Rev. 1992; 125: 77-97Crossref PubMed Scopus (152) Google Scholar, 4Fujiwara H. Kikutani H. Suematsu S. Naka T. Yoshida K. Yoshida K. Tanaka T. Suemura M. Matsumoto N. Kojima S. Kishimoto T. Yoshida N. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 6835-6839Crossref PubMed Scopus (144) Google Scholar, 5Yu P. Kosco-Vilbois M.H. Richards M. Kohler G. Lamers M.C. Nature. 1994; 369: 753-756Crossref PubMed Scopus (206) Google Scholar). CD23 is cleaved by membrane-associated metalloproteases (6Bailey S. Bolognese B. Buckle D.R. Faller A. Jackson J. Flamberg P.L. McCord M. Mayer R.J. Marshall L.A. Smith D.G. Bioorg. Med. Chem. Lett. 1998; 8: 23-28Crossref PubMed Scopus (15) Google Scholar, 7Marolewski A.E. Buckle D.R. Christie G. Earnshaw D.L. Flamberg P.L. Marshall L.A. Smith D.G. Mayer R.J. Biochem. J. 1998; 333: 573-579Crossref PubMed Scopus (39) Google Scholar) to yield soluble CD23 (sCD23) 6The abbreviations used are:sCD23soluble CD23VnRvitronectin receptorVnvitronectinFnfibronectinHIVhuman immunodeficiency virusHRPhorseradish peroxidaseOGPoctyl-β-d-glucopyranosideGSTglutathione S-transferasesiRNAsmall interference RNAPFHMprotein-free hybridoma medium-IILCDlow cell densitymAbmonoclonal antibodyTdRtritiated thymidineSPRsurface plasmon resonanceLPlong peptidePEphycoerythrinFITCfluorescein isothiocyanate proteins with molecular masses ranging from 37 to 16 kDa, all of which retain the capacity to regulate IgE synthesis; human sCD23 proteins exhibit pleiotropic cytokine-like activities (1Gould H.J. Sutton B.J. Beavil A.J. Beavil R.L. McCloskey N. Coker H.A. Fear D. Smurthwaite L. Annu. Rev. Immunol. 2003; 21: 579-628Crossref PubMed Scopus (539) Google Scholar, 2Bonnefoy J.-Y. Lecoanet-Henchoz S. Gauchat J.F. Graber P. Aubry J.P. Jeannin P. Plater-Zyberk C. Int. Rev. Immunol. 1997; 16: 113-128Crossref PubMed Scopus (68) Google Scholar, 3Delespesse G. Sarfati M. Wu C.Y. Fournier S. Letellier M. Immunol. Rev. 1992; 125: 77-97Crossref PubMed Scopus (152) Google Scholar). In the B cell compartment, sCD23 inhibits apoptosis of germinal center centrocytes and promotes their differentiation into plasmablasts (8Liu Y.-J. Mason D.Y. Johnson G.D. Abbot S. Gregory C.D. Hardie D.L. Gordon J. MacLennan I.C.M. Eur. J. Immunol. 1991; 21: 1905-1910Crossref PubMed Scopus (395) Google Scholar), at least in part by binding to CD21 (9Bonnefoy J.-Y. Henchoz S. Hardie D. Holder M.J. Gordon J. Eur. J. Immunol. 1993; 23: 969-972Crossref PubMed Scopus (103) Google Scholar), and sCD23 also inhibits apoptosis in pre-B cell lines (10White L.J. Ozanne B.W. Graber P. Aubry J.-P. Bonnefoy J.-Y. Cushley W. Blood. 1997; 90: 234-243Crossref PubMed Google Scholar) through, as we report here, an interaction with the αvβ5 integrin. In association with interleukin-1α, sCD23 promotes differentiation of monocytes and early thymocyte precursors (11Mossalayi M.D. Lecron J.-C. Dalloul A.H. Sarfati M. Bertho J.-M. Hofstetter H. Delespesse G. Drbre P. J. Exp. Med. 1990; 171: 959-964Crossref PubMed Scopus (95) Google Scholar) and, via binding to the αMβ2 (CD11b-CD18), αXβ2 (CD11c-CD18) (12Lecoanet-Henchoz S. Gauchat J.-F. Aubry J.P. Graber P. Life P. Paul-Eugene N. Ferrua B. Corbi A.L. Dugas B. Plater-Zyberk C. Bonnefoy J.-Y. Immunity. 1995; 3: 119-125Abstract Full Text PDF PubMed Scopus (134) Google Scholar), and αvβ3 integrins (13Hermann P. Armant M. Brown E. Rubio M. Ishihara H. Ulrich D. Caspary R.G. Lindberg F.P. Armitage R. Maliszewski C. Delespesse G. Sarfati M. J. Cell Biol. 1999; 144: 767-775Crossref PubMed Scopus (72) Google Scholar), stimulates tumor necrosis factor-α and interleukin-1α production by monocytes. soluble CD23 vitronectin receptor vitronectin fibronectin human immunodeficiency virus horseradish peroxidase octyl-β-d-glucopyranoside glutathione S-transferase small interference RNA protein-free hybridoma medium-II low cell density monoclonal antibody tritiated thymidine surface plasmon resonance long peptide phycoerythrin fluorescein isothiocyanate The structures of the derCD23 protein, a naturally occurring sCD23 fragment generated by action of the derp1 protease from Dermatophagoides pteronyssinus, and of a 25-kDa sCD23 (residues 150-321), have recently been solved by heteronuclear nuclear magnetic resonance spectroscopy (14Hibbert R.G. Teriete P. Grundy G.J. Beavil R.L. Reljic R. Holers V.M. J.P. Sutton B.J. H.J. J. Exp. Med. PubMed Scopus Google Scholar) and Full Text Full Text PDF PubMed Scopus Google Scholar), are between the structures derived by the both a for the lectin head β and (14Hibbert R.G. Teriete P. Grundy G.J. Beavil R.L. Reljic R. Holers V.M. J.P. Sutton B.J. H.J. J. Exp. Med. PubMed Scopus Google Scholar, Full Text Full Text PDF PubMed Scopus Google Scholar). The a of and of the lectin head and that the interaction for IgE and CD21 binding are (14Hibbert R.G. Teriete P. Grundy G.J. Beavil R.L. Reljic R. Holers V.M. J.P. Sutton B.J. H.J. J. Exp. Med. PubMed Scopus Google the also that that these binding and the structures for of cytokine-like activities are M.D. M. Delespesse G. Hofstetter H. B. Dalloul A.H. E. P. Sarfati M. J. 1992; PubMed Scopus Google Scholar). The that CD23 a binding in the lectin head and that in the CD23 in this Full Text Full Text PDF PubMed Scopus Google Scholar). The binding for integrins not in and, as here, this at the region of the lectin The αvβ5 integrin is a of the vitronectin receptor are of the integrin in association with of β A. A. Cell PubMed Scopus Google Scholar) and have in cell and from and Rev. PubMed Scopus Google Scholar, 1998; PubMed Scopus Google Scholar, J. Cell Sci. PubMed Scopus Google Scholar, J.F. Biol. PubMed Scopus Google Scholar). bind to the proteins vitronectin and fibronectin by of an motif in proteins E. Annu. Rev. Cell Biol. Scopus Google both the and β integrin to binding J.-P. T. B. R. R. D.L. A. PubMed Scopus Google Scholar, J.-P. T. R. A. M. PubMed Scopus Google Scholar). are to bind to proteins via peptide motifs E. Annu. Rev. Cell Biol. Scopus Google Scholar), in of the of of the RGD In αvβ5 to a the A. W. M.D. E. J. Cell Biol. 1993; PubMed Scopus Google Scholar), for this interaction has been the affinity of αvβ5 for the with an A. W. M.D. E. J. Cell Biol. 1993; PubMed Scopus Google Scholar) that ligands with the αvβ5 binding and have signaling This report that the αvβ5 integrin with sCD23 a from the RGD binding and that of a motif CD23 that is from interaction for of human pre-B for integrin and and αvβ5 from from from isothiocyanate and and phycoerythrin proteins by and for from and including and octyl-β-d-glucopyranoside by from 25-kDa with an in and by from The derCD23 a from J. of a of CD23 to as from from and from Cell and cell derived from a with R.G. PubMed Scopus Google and cell lines from Cell lines in with and and at 37 in a in in a as L.A. Ozanne B.W. Biol. PubMed Scopus Google Scholar). from used at a cells also in protein-free hybridoma medium-II at cell In cells at cell density a density at which the cells are to apoptosis (10White L.J. Ozanne B.W. Graber P. Aubry J.-P. Bonnefoy J.-Y. Cushley W. Blood. 1997; 90: 234-243Crossref PubMed Google Scholar). and cells in to at in the of at 37 for by of tritiated thymidine for to by the the the of in of of to at This to a that been with cells in of containing The and and as a and for binding of CD23, and integrin cells with for antibody a in the of a and of cells in in of in and with of a The at for at and the at for at to with and at for The and proteins to and at The and the and by in and to a to and with by an antibody and far-Western integrin proteins to and to The with in the of and binding and of the by containing and for of the and of of the 25-kDa sCD23 sequence synthesized by and peptides and peptides with synthesized by the peptide synthesized as a a common to which a is the The sequence a to The and the long peptide sequence are peptides and with αvβ5 integrin to and binding by of and by as of peptides to cells with and derived the In cell peptides used in the to and and and peptides in between peptides and αvβ5 integrin at a The αvβ5 integrin at a and an cell as a peptides in the and at a of with a association by a In all peptides to the binding to the and of a to D.G. J. 1999; PubMed Scopus Google Scholar), and to The αvβ5 a sCD23 of an human pre-B cell R.G. PubMed Scopus Google Scholar), from low cell apoptosis in a (10White L.J. Ozanne B.W. Graber P. Aubry J.-P. Bonnefoy J.-Y. Cushley W. Blood. 1997; 90: 234-243Crossref PubMed Google Scholar) sCD23 is the cytokine that cells from apoptosis cells not CD23 of (10White L.J. Ozanne B.W. Graber P. Aubry J.-P. Bonnefoy J.-Y. Cushley W. Blood. 1997; 90: 234-243Crossref PubMed Google Scholar) and not and this that the interaction of sCD23 with pre-B cells via a affinity of of cells proteins of and kDa, molecular masses that are with of and integrin not The that these and by affinity of cell by and proteins in the from the CD23 not in the from the The used in this to a that is the 25-kDa fragment generated of S. R. H. T. M.D. E. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). in the from the in cell not cells with both the that recognizes the αvβ5 J. Cell Biol. 1991; PubMed Scopus Google Scholar), and not with the J. Cell Biol. 1991; PubMed Scopus Google Scholar) of RNA of the for and for not The that cells αvβ5 and that with CD23 that this integrin is to pre-B cell growth and this cells with monoclonal with and the ligands for αvβ5. with the of cells in to of an without a pre-B cell also by the The that recognizes αvβ5 not αvβ5 binding to Smith 1995; PubMed Scopus Google Scholar), the which recognizes a αvβ5 and αvβ5 binding to J. Cell Biol. 1991; PubMed Scopus Google Scholar), to are of of and (13Hermann P. Armant M. Brown E. Rubio M. Ishihara H. Ulrich D. Caspary R.G. Lindberg F.P. Armitage R. Maliszewski C. Delespesse G. Sarfati M. J. Cell Biol. 1999; 144: 767-775Crossref PubMed Scopus (72) Google Scholar) that an to the RGD binding not production of cytokine by that of cells the that the binding for ligands and sCD23 are that αvβ5 regulates a in pre-B cell lines and that this to be both and independent of the integrin binding for The of an RGD sequence in sCD23 that the motif CD23 recognized by the integrin is not an sequence is an RGD sequence of this of to for is the interaction of αvβ5 with a motif of the A. W. M.D. E. J. Cell Biol. 1993; PubMed Scopus Google of CD23 by integrin in the sequence of 25-kDa from to used as the sequence for of the of of the is the sequence the CD23 sequence that with αvβ5 integrin. The lines the RKC-containing peptides that bind the αvβ5 integrin. of the CD23 is in B the lectin head and the loop the region of the the RKC motif recognized by the αvβ5 integrin αvβ5 integrin a and of the peptides at binding for peptides and, as a peptide the binding of the in with peptides and the are for of for binding of at the a association for derCD23 and of peptides and for αvβ5 integrin. binding of CD23 to cells in the of an of peptide peptide binding of peptide in the of binding of is in the αvβ5 a in sequence of 25-kDa human CD23 to is in with a of CD23 the of the of the 25-kDa sCD23 sequence and with αvβ5 to binding for the integrin. αvβ5 and to a of peptides not and the common to these peptides is a of sequence at in the CD23 The for sCD23 (14Hibbert R.G. Teriete P. Grundy G.J. Beavil R.L. Reljic R. Holers V.M. J.P. Sutton B.J. H.J. J. Exp. Med. PubMed Scopus Google Scholar, Full Text Full Text PDF PubMed Scopus Google Scholar) demonstrate that the RKC motif in a small disulfide-bonded loop at the of the lectin The interaction between the RKC-containing peptides and αvβ5 by surface plasmon resonance This that the RKC-containing peptides bind to αvβ5 integrin in a of peptide which not have an RKC motif, to bind to the integrin all by peptides to binding to αvβ5 the RKC The of the the RKC motif may be for the integrin the binding may the small common RKC tripeptide a for the binding of derCD23 to αvβ5 the affinity of this interaction is of the of as for binding of derCD23 to CD21 and to the region of human IgE (14Hibbert R.G. Teriete P. Grundy G.J. Beavil R.L. Reljic R. Holers V.M. J.P. Sutton B.J. H.J. J. Exp. Med. PubMed Scopus Google Scholar). the of of peptides to and long peptide for αvβ5 integrin. the with the in and the peptides for the integrin to that of between affinity of a peptide for αvβ5 and biological of αvβ3 integrin the surface not The demonstrate that RKC-containing peptides bind to αvβ5 integrin. that the binding of CD23 to cells by inclusion of peptide not by a of peptide the and have been by also binding of CD23 to the cells not the CD23 the binding of peptide to that CD23 and peptides derived from for binding to the RKC-containing to and of that RKC-containing peptides bind to αvβ5 in The binding of peptides to cells by and all RKC-containing peptides to cells and and to pre-B cell lines as not peptides to peptides and and peptide that to the peptides that to a all to bind to αvβ5 to cells which have an tripeptide peptides that have the RGD also not bind to αvβ5 to cells not of peptide to cells by the of peptides and not peptide and a for cells not The binding of the αvβ5 to pre-B cells that binding of this peptide to the integrin the cell surface the of the integrin that the of the recognized by the antibody is the of αvβ5 to binding of peptides and CD23 by an RNA not to deliver to pre-B cell lines to a in integrin RNA in these cells not an for the subunit into human and the of integrins and binding of CD23 and peptides to the cells The subunit of of all integrins to the requirement for and β to in the to to the cell the subunit with A. A. Cell PubMed Scopus Google Scholar), a of also αvβ5 cell surface that of to not the by the and and both and αvβ5 at the cell surface the of with the unaffected by binding of CD23 peptide to cells by a the binding of a peptide that of integrin in and with a of binding of CD23 and RKC-containing peptides to the that integrins are the for CD23 the also and integrin the of which be unaffected by is that of these integrins, and in the integrin for in binding are with the of which that CD23 the αvβ5 integrin. The biological activities of peptides in low cell density and thymidine by that peptides that bind αvβ5 via their RKC motif the of CD23 peptides and which to not the that these peptides as of the activity of peptides and cells with an of peptides and with peptide both peptide and peptides and the peptide not and that peptides and the action of peptides and in a of sequence to binding of RKC-containing peptides to cells of of the cells by peptides and and demonstrate that the integrin not the RGD binding to sCD23 of the IgE and CD21 that αvβ5 integrin recognizes the peptide region in CD23 by and in peptides and with and a to growth of cells with peptide to that with peptide peptide binding to cells and that all peptide binding to αvβ5 integrin the of peptide with for peptide which at to with peptide and which also binding to cells not the of binding to αvβ5 and to cells and the peptide to bind to αvβ5 as by a of CD23 which the RKC motif the RGD motif, the CD21 and IgE interaction and all that in of binding in the lectin head Full Text Full Text PDF PubMed Scopus Google Scholar), growth of cells in a The for the in the is to that for 25-kDa sCD23 (10White L.J. Ozanne B.W. Graber P. Aubry J.-P. Bonnefoy J.-Y. Cushley W. Blood. 1997; 90: 234-243Crossref PubMed Google Scholar) The the RKC motif by also growth of cells the that the RKC motif is and for of sCD23 cytokine activity in The are with the that the cytokine activity of CD23 via the αvβ5 integrin in pre-B cells not from the motif from the IgE and CD21 binding sites. RKC-containing from CD23 β of that the RKC-containing peptides not bind to the RGD binding of the integrins, and this is by the for αvβ3 in association with an that that the is to be in the RGD binding J.-P. T. R. A. M. PubMed Scopus Google Scholar). a in the binding for RKC-containing peptides in the αvβ5 integrins, a far-Western in which αvβ5 and αvβ3 integrins and the to and with RKC-containing and that peptide to the and at to the of with an peptide and that binding of peptide to the subunit is not by the of peptide of of the inclusion of peptide binding of peptide to the subunit by are with of that peptide peptide of The of that RKC-containing peptides bind to a present the β of the integrins. This the αvβ5 integrin as a CD23 the for the integrin the CD23 protein, and a for CD23 in of human B cell The demonstrate that signaling via the integrin is and is via a the integrin that is from the RGD binding and recognizes a this to the β the protein-free of the and the of the ligands the demonstrate that integrins important signals to cells without the for of the RGD binding This may not be to αvβ5. The the of CD23 in human B cell and that the pleiotropic functions of CD23 are by motifs the The RKC motif recognized by the αvβ5 integrin is at of the human CD23 and is in all forms of sCD23 that cytokine activity (1Gould H.J. Sutton B.J. Beavil A.J. Beavil R.L. McCloskey N. Coker H.A. Fear D. Smurthwaite L. Annu. Rev. Immunol. 2003; 21: 579-628Crossref PubMed Scopus (539) Google Scholar). the RKC motif in the of in the CD23 and that the integrin binding is from used to IgE CD21 (14Hibbert R.G. Teriete P. Grundy G.J. Beavil R.L. Reljic R. Holers V.M. J.P. Sutton B.J. H.J. J. Exp. Med. PubMed Scopus Google Scholar). is also from the sequence in the region to bind to II A. Biochem. PubMed Scopus Google Scholar). The by the of derCD23 (14Hibbert R.G. Teriete P. Grundy G.J. Beavil R.L. Reljic R. Holers V.M. J.P. Sutton B.J. H.J. J. Exp. Med. PubMed Scopus Google Scholar) and of sCD23 Full Text Full Text PDF PubMed Scopus Google Scholar) the RKC in a small disulfide-bonded loop the of the lectin at a between the and with the of Cys174 in of a with and The of of binding and activity of peptide the and are with a for these the of the loop in binding to the integrin. The of peptide to binding of sCD23 to cells this structures for derCD23 with to the RKC motif is that Cys174 by of with and is also in Arg172, the of the a of The of sCD23 and the of derCD23 and in the of the RKC motif, both and are to the in the derCD23 the sCD23 a to the and the in a and and binding of in the of sCD23 as a Full Text Full Text PDF PubMed Scopus Google Scholar), is the and of the RKC in the and The a binding for the both and for the not an in which an of that the structures to that a interaction surface of the human and in the of the αvβ5 binding in this report a for the of cytokine-like activity in CD23 via the integrins. The human CD23 sequence between and is the sequence is the RKC motif that may be the of binding and activity is to in the CD23 In to the and may both and to a binding may the to bind to the integrin in a of signaling to the cell is to be the of cytokine activity, is a for binding and, by biological The of demonstrate that αvβ5 ligands and and to of αvβ5 in pre-B cell lines by acting via and binding αvβ5. are for signaling via αvβ3 in monocytes CD23 promotes cytokine cell cytokine production (13Hermann P. Armant M. Brown E. Rubio M. Ishihara H. Ulrich D. Caspary R.G. Lindberg F.P. Armitage R. Maliszewski C. Delespesse G. Sarfati M. J. Cell Biol. 1999; 144: 767-775Crossref PubMed Scopus (72) Google Scholar). The of interactions between pre-B cells cells with cells for is the interaction J. A. K. D. J. PubMed Scopus Google Scholar, A. K. D. J. 1994; 8: Google Scholar, 1993; Google and, in the ligands are present and S. PubMed Scopus Google Scholar) and CD23 C. M. S. H. E. P. 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