We previously reported that MOLT-3 human lymphocyte-like leukemia cells adhere to tissue-type transglutaminase (tTG) through the integrin ␣ 4 ␤ 1 . We now report that G-361 human melanoma cells also adhere to tTG, although they do not express ␣ 4 ␤ 1 . G-361 cells utilize two additional integrins, ␣ 9 ␤ 1 and ␣ 5 ␤ 1 to adhere to tTG. Furthermore, blood coagulation factor XIII (FXIII), another member of the transglutaminase family that is highly homologous to tTG, and propolypeptide of von Willebrand factor (pp-vWF) also promoted cell adhesion through ␣ 9 ␤ 1 or ␣ 4 ␤ 1 in G-361 or MOLT-3 cells, respectively. In the case of pp-vWF, ␣ 9 ␤ 1 and ␣ 4 ␤ 1 both bind to the same site, comprised of 15 amino acid residues and designated T2-15. Moreover, SW480 human colon cancer cells stably transfected to express ␣ 9 ␤ 1 , but not mock transfectants, adhered to tTG, FXIII, pp-vWF, and T2-15/ bovine serum albumin conjugate. These data identify tTG, FXIII, and pp-vWF as shared ligands for the integrins ␣ 9 ␤ 1 and ␣ 4 ␤ 1 . This report is the first to unambiguously show that these two integrins share the same cell adhesion site within one protein and provides strong support for classifying ␣ 9 ␤ 1-and ␣ 4 -integrins as functionally related members of an integrin subfamily.Integrins are a family of heterodimeric transmembrane receptors that mediate cell-extracellular matrix and cell-cell interactions and play important roles in a wide variety of cellular events (1-6). Each integrin is composed of noncovalently associated ␣ and ␤ subunits, and the combination of ␣ and ␤ subunits generates many different receptors with different ligand specificity.Integrin ␣ subunits can be grouped into subfamilies based on sequence similarity, and these subfamilies generally define integrins that share common ligands. Thus, ␣ subunits can be divided into five groups (6 -8): the first group (␣ 1 , ␣ 2 , ␣ 10 , and ␣ 11 ) recognizes collagen, the second group (␣ 3 , ␣ 6 , and ␣ 7 ) recognizes laminin, the third group (␣ 5 , ␣ 8 , ␣ v , and ␣ IIb ) recognizes RGD-containing sequences, and the fourth group (␣ L , ␣ M , ␣ X , and ␣ D ) recognizes ICAM-1. ␣ 4 and ␣ 9 are the only members of the fifth group (9). Somewhat surprisingly, the initial ligands identified for ␣ 9 and ␣ 4 -containing integrins did not appear to overlap. Thus, for example, the integrin ␣ 4 ␤ 1 was found to recognize fibronectin (10, 11) and the vascular cell adhesion molecule-1 (VCAM-1) 1 as ligands (12), whereas the integrin ␣ 9 ␤ 1 was reported to recognize tenascin-C, (13,14), and osteopontin (15, 16). However, recently Bayless et al. (17) reported that ␣ 4 ␤ 1 recognizes osteopontin as a ligand, and Taooka et al. (18) reported that ␣ 9 ␤ 1 recognizes VCAM-1. It thus appears that the ␣ 4 ␤ 1-and ␣ 9 ␤ 1 -integrins, like other integrins that are related based on ␣ subunit sequence homology, do share at least some common ligands.In the present study, we demonstrate that three additional proteins are ligands for both ␣ 9 ␤ 1 and ␣ 4 ␤ 1 . The first is a tissue-type trans...

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