CD47 (integrin-associated protein) is an integral membrane protein that is required for granulocyte and T cell recruitment to sites of infection (1, 2), and its absence on red blood cells leads to their rapid macrophage-mediated clearance (3). CD47 may also function as a costimulator to regulate T cell activation, survival, and Th1 versus Th2 differentiation (4, 5). Endogenous ligands for the extracellular domain of CD47 include the secreted protein thrombospondin-1 (TSP1) 1 and potentially other members of the thrombospondin family, several integrins (6 -9), and some members of the signal-regulatory protein family (3, 10 -13). Engagement of CD47 by soluble ligands or signal-regulatory protein counter receptors modulates several cell signaling pathways, including activation of a heterotrimeric G protein (14).Although some signal transduction through CD47 is integrin-independent (4, 15, 16), association of CD47 with certain integrins was found to modulate their function to mediate cell adhesion or motility (6,8,9,17). In addition to its known functional and physical interactions with ␣ v ␤ 3 , ␣ IIb ␤ 3 , and ␣ 2 ␤ 1 integrins, several publications have suggested an association of CD47 with ␣ 4 ␤ 1 integrin. CD47 and ␣ 4 ␤ 1 were colocalized on microvilli of K562 erythroleukemia cells (18), and CD47-dependent arrest of T cells on inflammatory endothelium could be blocked by antibodies that prevent ␣ 4 ␤ 1 integrin binding to VCAM-1 (2). In the latter study, ligation of CD47 by TSP1 or signal-regulatory protein 1␣ was inferred to activate ␣ 4 ␤ 1 integrin on T cells, although this was not demonstrated either functionally or biochemically.We recently found that CD47 expression is required for stimulation of T cell motility and expression of MMP-2 stimulated by ␣ 4 ␤ 1 integrin ligands (19). An antibody to CD47 also blocked the motility response to an ␣ 4 ␤ 1 integrin ligand (19). Therefore, at least a functional interaction occurs between CD47 and ␣ 4 ␤ 1 integrin.We identified a binding site for ␣ 4 ␤ 1 integrin in the Nterminal domains of TSP1 and TSP2 (19), whereas two binding sites for CD47 have been localized to the C-terminal domain of TSP1 (for review, see Ref. 20). Thus, TSP1 could potentially regulate its own interaction with ␣ 4 ␤ 1 integrin through simultaneous interactions with CD47 and ␣ 4 ␤ 1 integrin on a T cell, analogous to the ability of soluble TSP1 to stimulate ␣ v ␤ 3 integrin-dependent melanoma cell adhesion to immobilized TSP1 (21).To define a molecular basis for functional cross-talk between these two receptors, we have examined the effect of CD47 ligands on the function of ␣ 4 ␤ 1 integrin in T cells and melanoma cells. We confirmed that ligation of CD47 can activate ␣ 4 ␤ 1 integrin function but unexpectedly found the mechanism of this activity to be CD47 ligand-dependent. We further show that CD47 ligation differentially activates and inactivates ␣ v ␤ 3 and ␣ 4 ␤ 1 in melanoma cells and ␣ 4 ␤ 1 and ␣ 5 ␤ 1 in Jurkat cells. Unexpectedly, but consistent with a recent report demonstrating C...

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Identification of new potential markers that may help in the diagnosis of benign and malignant thyroid lesions is needed. By comparative 2-dimensional gel electrophoresis of microdissected cells from tumors and normal thyroid tissue, we identified a new protein, S100C, which is highly expressed in papillary carcinomas. In order to validate this finding, we investigated the immunohistochemical expression and the potential role in diagnosis of these markers in 94 specimens representing the spectrum of malignant and benign thyroid lesions. Normal thyroid tissue was evaluated in 57 specimens. Galectin-3, a marker reported as specific for malignant lesions, was also evaluated in the same lesions. S100C protein was expressed in the nuclei of normal tissue, hyperplastic nodules, and follicular adenomas and carcinomas. Papillary carcinomas showed a strong, but cytoplasmic, pattern of staining. Galectin-3 immunostaining was strongly positive in papillary carcinomas, and negative in benign lesions, confirming its value in differential diagnosis. These findings suggest that immunohistochemical staining of S100C could be helpful in the pathological study of thyroid lesions, especially in cases in which follicular variants of papillary carcinoma and follicular carcinoma are considered in the differential diagnosis.