The Ras superfamily of small GTPases is composed of more than 150 members, which share a conserved structure and biochemical properties, acting as binary molecular switches turned on by binding GTP and off by hydrolyzing GTP to GDP. However, despite considerable structural and biochemical similarities, these proteins play multiple and divergent roles, being versatile and key regulators of virtually all fundamental cellular processes. Conversely, their dysfunction plays a crucial role in the pathogenesis of serious human diseases, including cancer and developmental syndromes. Fuelled by the original identification in 1982 of mutationally activated and transforming human Ras genes in human cancer cell lines, a variety of powerful experimental techniques have been intensively focused on discovering and studying structure, biochemistry, and biology of Ras and Ras-related small GTPases, leading to fundamental research breakthroughs into identification and structural and functional characterization of a huge number of Ras superfamily members, as well as of their multiple regulators and effectors. In this review we provide a general overview of the major milestones that eventually allowed to unlock the secret treasure chest of this large and important superfamily of proteins.

The ␤1-integrin cytoplasmic domain consists of a membrane proximal subdomain common to the four known isoforms ("common" region) and a distal subdomain specific for each isoform ("variable" region). To investigate in detail the role of these subdomains in integrin-dependent cellular functions, we used ␤1A and ␤1B isoforms as well as four mutants lacking the entire cytoplasmic domain (␤1TR), the variable region (␤1COM), or the common region (␤1⌬COM-B and ␤1⌬COM-A). By expressing these constructs in Chinese hamster ovary and ␤1 integrin-deficient GD25 cells (Wennerberg et al., J Cell Biol 132, 227-238, 1996), we show that ␤1B, ␤1COM, ␤1⌬COM-B, and ␤1⌬COM-A molecules are unable to support efficient cell adhesion to matrix proteins. On exposure to Mn ϩϩ ions, however, ␤1B, but none of the mutants, can mediate cell adhesion, indicating specific functional properties of this isoform. Analysis of adhesive functions of transfected cells shows that ␤1B interferes in a dominant negative manner with ␤1A and ␤3/␤5 integrins in cell spreading, focal adhesion formation, focal adhesion kinase tyrosine phosphorylation, and fibronectin matrix assembly. None of the ␤1 mutants tested shows this property, indicating that the dominant negative effect depends on the specific combination of common and B subdomains, rather than from the absence of the A subdomain in the ␤1B isoform. INTRODUCTIONIntegrins are ␣/␤ heterodimeric transmembrane cell surface receptors that mediate cell adhesion and migration and also the bidirectional transfer of information across the plasma membrane. These properties are essential in regulating several biological processes, including morphogenesis, immune response, cell growth, differentiation, and survival (Hynes, 1992;Ruoslahti and Reed, 1994).The cytoplasmic domains of integrin subunits are required for these functions (Hibbs et al., 1991;Yamada and Miyamoto, 1995;Dedhar and Hannigan, 1996). In vitro, the isolated ␤1 cytoplasmic domain was shown to bind talin, ␣-actinin, and paxillin, three cytoskeletal proteins that mediate the anchorage of actin filaments to the plasma membrane (Chen et al., 1995;Otey et al., 1993;Schaller et al., 1995). Binding of the ␤1 cytoplasmic sequence to focal adhesion kinase (FAK), a tyrosine kinase specifically localized to focal adhesions, and to the serine/threonine kinase integrin-linked kinase has also been reported Hannigan et al., 1996). In vivo, the ␤1 cytoplasmic domain is sufficient for its localization to preformed focal adhesions (LaFlamme et al., 1992, Akiyama et al., 1994 and for the initiation of signaling to FAK (Lukashev et al., 1994). A model has been proposed in which the ␤1 subunit cytoplasmic domain ‡ Corresponding author.© 1998 by The American Society for Cell Biology 715contains a default signal for interaction with cytoskeletal molecules that is masked by the ␣ subunit cytoplasmic domain (Briesewitz et al., 1993;Ylanne et al., 1993). In response to matrix ligands or to multivalent antibody binding, the inhibitory effect of the ␣ subunit can be release...

Vitamin D deficiency has been clearly linked to major chronic diseases associated with oxidative stress, inflammation, and aging, including cardiovascular and neurodegenerative diseases, diabetes, and cancer. In particular, the cardiovascular system appears to be highly sensitive to vitamin D deficiency, as this may result in endothelial dysfunction and vascular defects via multiple mechanisms. Accordingly, recent research developments have led to the proposal that pharmacological interventions targeting either vitamin D deficiency or its key downstream effects, including defective autophagy and abnormal pro-oxidant and pro-inflammatory responses, may be able to limit the onset and severity of major cerebrovascular diseases, such as stroke and cerebrovascular malformations. Here we review the available evidence supporting the role of vitamin D in preventing or limiting the development of these cerebrovascular diseases, which are leading causes of disability and death all over the world.

The coordinate modulation of the cellular functions of cadherins and integrins plays an essential role in fundamental physiological and pathological processes, including morphogenesis, tissue differentiation and renewal, wound healing, immune surveillance, inflammatory response, tumor progression, and metastasis. However, the molecular mechanisms underlying the fine-tuned functional communication between cadherins and integrins are still elusive. This paper focuses on recent findings towards the involvement of reactive oxygen species (ROS) in the regulation of cell adhesion and signal transduction functions of integrins and cadherins, pointing to ROS as emerging strong candidates for modulating the molecular crosstalk between cell-matrix and cell-cell adhesion receptors.