ROLE OF ADHESION MOLECULE CYTOPLASMIC DOMAINS IN MEDIATING INTERACTIONS WITH THE CYTOSKELETON

The past ten years have seen significant progress in cell biology rese arch aimed at understanding how cytoskeletal filaments interact with t he plasma membrane. Considerable evidence suggests that both actin mic rofilaments and intermediate filaments attach to the membrane via the cytoplasmic domains of various membrane proteins including adhesion mo lecules. Interactions between the cytoskeleton and adhesion molecules appear to be essential for a variety of cellular functions, including cell-cell and cell-extracellular matrix (ECM) interactions, cell motil ity, receptor-ligand interactions, and receptor internalization. Recen tly, many of the detailed molecular mechanisms which mediate the assoc iations between actin filaments and adhesion molecules have been ident ified. Among adhesion molecules that support the attachment of cytoske letal filaments to their cytoplasmic domains are members of the integr in and cadherin families, the intracellular adhesion molecule-1 (ICAM- 1, an immunoglobulin family member), and the glycoprotein Ib/IX comple x in platelets. A general conclusion emerging from these studies is th at physical associations between cytoskeletal filaments and transmembr ane glycoproteins do not occur directly between the filaments and the cytoplasmic tails of adhesion molecules. Instead, these interactions a ppear to be indirect and involve a complex ensemble of intermediary li nker proteins. The severe effects of cytoplasmic domain deletion and m utagenesis on adhesion-dependent functions support the view that recep tor cytoplasmic domains play a vital role in regulating receptor funct ion and in mediating communication across the membrane. Transfection s tudies with mutant and chimeric adhesion molecules, along with protein -binding studies, are clarifying the mechanisms which physically link the cytoskeleton to transmembrane proteins, regulate cytoskeletal orga nization, mediate signaling across the cell membrane, and regulate the ligand specificity and binding affinity of surface receptors.