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The beta subunit cytoplasmic domains of integrin adhesion receptors are necessary for the connection of these receptors to the actin cytoskeleton. The cytoplasmic protein, talin, binds to beta integrin cytoplasmic tails and actin filaments, hence forming an integrin-cytoskeletal linkage. We used recombinant structural mimics of beta(1)A, beta(1)D and beta(3) integrin cytoplasmic tails to characterize integrin-binding sites within talin. Here we report that an integrin-binding site is localized within the N-terminal talin head domain. The binding of the talin head domain to integrin beta tails is specific in that it is abrogated by a single point mutation that disrupts integrin localization to talin-rich focal adhesions. Integrin-cytoskeletal interactions regulate integrin affinity for ligands (activation). Overexpression of a fragment of talin containing the head domain led to activation of integrin alpha(IIb)beta(3); activation was dependent on the presence of both the talin head domain and the integrin beta(3) cytoplasmic tail. The head domain of talin thus binds to integrins to form a link to the actin cytoskeleton and can thus regulate integrin function.
Integrins are major two-way signaling receptors responsible for the attachment of cells to the extracellular matrix and for cell-cell interactions that underlie immune responses, tumor metastasis, and progression of atherosclerosis and thrombosis. We report the structure-function analysis of the cytoplasmic tail of integrin beta 3 (glycoprotein IIla) based on the cellular import of synthetic peptide analogs of this region. Among the four overlapping cell-permeable peptides, only the peptide carrying residues 747-762 of the carboxyl-terminal segment of integrin beta 3 inhibited adhesion of human erythroleukemia (HEL) cells and of human endothelial cells (ECV) 304 to immobilized fibrinogen mediated by integrin beta 3 heterodimers, alpha IIb beta 3, and alpha v beta 3, respectively. Inhibition of adhesion was integrin-specific because the cell-permeable beta 3 peptide (residues 747-762) did not inhibit adhesion of human fibroblasts mediated by integrin beta 1 heterodimers. Conversely, a cell-permeable peptide representing homologous portion of the integrin beta 1 cytoplasmic tail (residues 788-803) inhibited adhesion of human fibroblasts, whereas it was without effect on adhesion of HEL or ECV 304 cells. The cell-permeable integrin beta 3 peptide (residues 747-762) carrying a known loss-of-function mutation (Ser752Pro) responsible for the genetic disorder Glanzmann thrombasthenia Paris I did not inhibit cell adhesion of HEL or ECV 304 cells, whereas the beta 3 peptide carrying a Ser752Ala mutation was inhibitory. Although Ser752 is not essential, Tyr747 and Tyr759 form a functionally active tandem because conservative mutations Tyr747Phe or Tyr759Phe resulted in a nonfunctional cell permeable integrin beta 3 peptide. We propose that the carboxyl-terminal segment of the integrin beta 3 cytoplasmic tail spanning residues 747-762 constitutes a major intracellular cell adhesion regulatory domain (CARD) that modulates the interaction of integrin beta 3-expressing cells with immobilized fibrinogen. Import of cell-permeable peptides carrying this domain results in inhibition "from within" of the adhesive function of these integrins.
The extracellular matrix plays important roles in embryogenesis. The integrin family of adhesion receptors may mediate critical cellular interactions with the extracellular matrix during development. In this study, we elucidated the developmental spatial and temporal expression pattern of the alpha 2 beta 1 integrin heterodimer, a cell surface receptor for collagens and laminin. We generated reagents for studying the alpha 2 beta 1 integrin and examined the developmental expression of the integrin in postimplantation mice. A partial length murine alpha 2 cDNA was isolated and the protein encoding region was found to be 82% homologous to that of the human alpha 2 cDNA. A synthetic peptide corresponding to the carboxy-terminus of murine alpha 2 was used to generate alpha 2-specific antiserum. The antiserum and riboprobes derived from both the alpha 2 cDNA and the previously characterized murine beta 1 subunit cDNA were used to determine the spatiotemporal expression of the alpha 2 subunit by immunocytochemistry and of the alpha 2 and beta 1 mRNAs by in situ hybridization. Both approaches gave concordant results. Expression of the alpha 2 integrin subunit was observed in both the maternal and embryonic components of the placenta, namely the perivascular and basal zone decidual cells and decidual cells and spongiotrophoblasts at the maternal/embryonic junction. Expression was also observed in cells actively producing and remodeling the extracellular matrix in the maternal uterus and in the developing gut, lens, cartilage, bone, and tooth of the embryo. Generally, expression of the alpha 2 integrin subunit was found in cells entering their later stages of differentiation such as in chondrocytes as they became hypertrophic, ameloblasts and odontoblasts as they became columnar and began to secrete the matrix of the tooth, endothelial cells after they formed tubules, in the lens just prior to and during lens fiber production, and in the collecting ducts of the kidney only after full gestation. Throughout embryogenesis, beta 1 mRNA was widely distributed and present in cell types expressing alpha 2 mRNA and protein. The developmental expression pattern of the alpha 2 beta 1 integrin suggests roles for the integrin in placental development and matrix assembly and remodeling.