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 ␣v␤5 integrin. The integrin recognizes a tripeptide motif in a small disulfidebonded loop at the N terminus of the lectin head region of CD23, centered around Arg 172 , Lys 173 , and Cys 174 (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. RKCcontaining peptides derived from this region of CD23 bind ␣v␤5 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 farWestern analyses, RKC-containing peptides bind to the ␤ subunit of the ␣v␤5 integrin. The interaction between ␣v␤5 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 ␣v␤5.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 (1-5). CD23 is cleaved by membrane-associated metalloproteases (6, 7) to yield soluble CD23 (sCD23) 6 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 (1-3). In the B cell compartment, sCD23 inhibits apoptosis of germinal center centrocytes and promotes their differentiation into plasmablasts (8), at least in part by binding to CD21 (9), and sCD23 also inhibits apoptosis in pre-B cell lines (10) through, as we report here, an interaction with the ␣v␤5 integrin. In association with interleukin-1␣, sCD23 promotes differentiation of monocytes and early thymocyte precursors (11) and, via binding to the ␣M␤2 (CD11b-CD18), ␣X␤2 (CD11c-CD18) (12), and ␣v␤3 integrins (13), stimulates tumor necrosis factor-␣ and interleukin-1␣ production by monocytes. 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 (14) and x-ray crystallography (15), respectively. Although there are pronounced differences between the structures derived by the two methods, both show a generally consistent overall structure for the C-type lectin head domain comprising eight ␤ sheets and two ␣ helices (14, 15). The NMR structure reveals a striking distribution of acidic and basic residues on opposites faces of t...

Gliotoxin is a potent NOTCH2 transactivation inhibitor and efficiently induces apoptosis in chronic lymphocytic leukaemia (CLL) cells

“…It is important to note that FCER2 gene products may exert growth factor activity for B cells (Borland et al, 2007) and that NR4A1 induces apoptosis in response to a broad range of stimuli including PMA and apoptotic BCR signalling (Mapara et al, 1995;Li et al, 2000). Taking into consideration that NOTCH interferes with the apoptotic function of NR4A1 (Lee et al, 2002), the observed upregulation of NR4A1 in response to PMA might mechanistically explain why PMA enhances the apoptotic effect of gliotoxin-mediated NOTCH2 inhibition.…”

SDF-1 and PDGF enhance αvβ5-mediated ERK activation and adhesion-independent growth of human pre-B cell lines

“…1 The interaction between soluble CD23 (sCD23) and the integrin avb5 sustains growth of human pre-B cell lines derived from ALL patients. 2,3 Human CD23, a 45-kDa type II transmembrane glycoprotein, can be cleaved from the cell surface to release a range of sCD23 proteins with cytokinelike activities. The cytokine-like activities include promoting the release of cytokines from monocytic cells, mediated by the aMb2, aXb2 4,5 and avb3 integrins, 6 and influencing the survival and differentiation of centrocytes by binding to CD21.…”

“…11 The avb5 integrin, a member of the vitronectin receptor family, is expressed by bone marrow B-cell precursors. 2 The vitronectin receptor family members comprise the av chain in non-covalent association with one of five b-subunits (b1, b3, b5, b6 and b8) and bind a broad spectrum of ligands, including fibrinogen, fibronectin and vitronectin, typically by the recognition of arg-gly-asp motifs. [12][13][14] Vitronectin receptors have diverse roles in cell adhesion, migration and survival and are implicated in the growth of a number of cancer cells.…”

“…[12][13][14] Vitronectin receptors have diverse roles in cell adhesion, migration and survival and are implicated in the growth of a number of cancer cells. The vitronectin receptors avb5 and avb3 are recognized CD23 receptors 2,6 and avb5 recognizes an arg-lys-cys (RKC) motif on sCD23 in an adhesionindependent interaction. 2 The growth and survival of normal and leukaemic B-cell progenitors is dependent on intimate contact with bone marrow stromal layers [15][16][17] and the factors responsible for the proliferation of progenitor cells include both cellular adhesion molecules and soluble proteins.…”

“…The vitronectin receptors avb5 and avb3 are recognized CD23 receptors 2,6 and avb5 recognizes an arg-lys-cys (RKC) motif on sCD23 in an adhesionindependent interaction. 2 The growth and survival of normal and leukaemic B-cell progenitors is dependent on intimate contact with bone marrow stromal layers [15][16][17] and the factors responsible for the proliferation of progenitor cells include both cellular adhesion molecules and soluble proteins. 15 The avb5-CD23 interaction could represent an important mechanism regulating the growth of B-cell precursors, in combination with other factors present in the bone marrow microenvironment.…”