Integrins as regulators of the mitotic machinery

Mitotic spindle bipolarity defines a unique division plane that promotes the successful transmission of genetic material during cytokinesis. The positioning and orientation of the spindle determines the symmetry of cell division and the relative location of daughter cells, which regulate cell fate decisions that contribute to embryonic development and tissue differentiation. Recent studies have identified integrins as regulators of spindle positioning and orientation, as well as spindle bipolarity and cytokinesis. This review summarizes and discusses the current effort focused on understanding how integrins regulate these mitotic events.     

Integrins

Integrins are cell adhesion receptors that are evolutionary old and that play important roles during developmental and pathological processes. The integrin family is composed of 24 αβ heterodimeric members that mediate the attachment of cells to the extracellular matrix (ECM) but that also take part in specialized cell-cell interactions. Only a subset of integrins (8 out of 24) recognizes the RGD sequence in the native ligands. In some ECM molecules, such as collagen and certain laminin isoforms, the RGD sequences are exposed upon denaturation or proteolytic cleavage, allowing cells to bind these ligands by using RGD-binding receptors. Proteolytic cleavage of ECM proteins might also generate fragments with novel biological activity such as endostatin, tumstatin, and endorepellin. Nine integrin chains contain an αI domain, including the collagen-binding integrins α1β1, α2β1, α10β1, and α11β1. The collagen-binding integrins recognize the triple-helical GFOGER sequence in the major collagens, but their ability to recognize these sequences in vivo is dependent on the fibrillar status and accessibility of the interactive domains in the fibrillar collagens. The current review summarizes some basic facts about the integrin family including a historical perspective, their structure, and their ligand-binding properties.     

Integrins as a distinct subtype of dependence receptors

In the absence of their cognate ligand, dependence receptors trigger programmed cell death. This function is the defining feature of dependence receptors, which include members of several different protein families. The integrins are a family of heterodimeric receptors for extracellular matrix (ECM) proteins, mediating cell anchorage and migration. Integrins share characteristics with dependence receptors, and integrin binding to substrate ECM ligands is essential for cell survival. Although integrins do not conform in all characteristics to the established definitions of dependence receptors, alterations in the expression of integrins and their ligands during physiological and pathological events, such as wound healing, angiogenesis and tumorigenesis, do regulate cell fate in a ligand-dependent manner. This biosensory function of integrins fits well with our current concept of dependence receptor action, and thus integrins may rightly be considered to comprise a distinct subclass of dependence receptor.     

Membrane proteins as light-energy transducers

Monoclonal antibodies to different parts of bacteriorhodopsin were raised to define its topography in the membrane. It is shown that the amino acid residue Glu 194 is a part of an antigenic determinant and should be located on the membrane surface. We found that the removal of the C-terminal 17 amino acid sequence does not affect the efficiency of the proton transport in bacteriorhodopsin. From a combination of proteolysis and secondary structure prediction methods an experimentally testable structural model for bovine rhodopsin is presented. The complete amino acid sequence of the transducin γ-subunit consisting of 69 residues was determined.     

G-proteins as transducers in transmembrane signalling

The G-protein-mediated signalling system has evolved as one of the most widely used transmembrane signalling mechanisms in mammalian organisms. All mammalian cells express G-protein-coupled receptors as well as several types of heterotrimeric G-proteins and effectors. G-protein-mediated signalling is involved in many physiological and pathological processes. This review summarizes some general aspects of G-protein-mediated signalling and focusses on recent data especially from studies in mutant mice which have elucidated some of the cellular and biological functions of heterotrimeric G-prtoteins.     

Integrins as a potential target for targeted anticancer therapy

The review briefly summarizes information of structure of integrins and their involvement in the development and malignant progression of tumors. Special attention is paid to approaches based on modification of functional properties of integrins that prevent/antagonize tumor growth and progression; these approaches developed in modern experimental biology have certain perspective in clinical application.     

Integrins and metastasis

Metastasis is a combination of biological events that makes the difference between cancer and other diseases. Metastasis requires flow of erroneous but precisely coordinated basic cellular activities like cell migration–invasion, cell survival–apoptosis, cell proliferation, etc. All of these processes require efficient regulation of cell attachment and detachment, which recruit integrin receptors in this flow of events. World literatures show several aspects of interrelation of integrins and metastasis. Integrin molecules are being used as prime target to battle metastasis. In this review we are collating the observations showing importance of integrin biology in regulation of metastasis and the strategies where integrin receptors are being used as targets to regulate metastasis.     

Integrins in mechanotransduction

Mechanical forces are crucial to the regulation of cell and tissue morphology and function. At the cellular level, forces influence cytoskeletal organization, gene expression, proliferation, and survival. Integrin-mediated adhesions are intrinsically mechanosensitive and a large body of data implicates integrins in sensing mechanical forces. We review the relationship between integrins and mechanical forces, the role of integrins in cellular responses to stretch and fluid flow, and propose that some of these events are mechanistically related.     

Phorbol esters as signal transducers and tumor promoters

Extracellular ligands transfer information into the cell through various signaling pathways which operate in an integrated way. Oncogene proteins and tumor promoters cooperate to constitutively turn on the signaling pathways and lead to irreversible cell activation. The evidence that supports this concept is reviewed, with emphasis on the role of phorbol esters and protein kinase C in signal transduction and oncogenesis.     

Integrins hold Drosophila together

The Drosophila position-specific (PS) integrins are members of the integrin family of cell surface receptors and are thought to be receptors for extracellular matrix components. Each PS integrin consists of an α subunit, α_PS1 or α_PS2, and a β_PS subunit. Mutations in the β_PS subunit and the α_PS2 subunit have been characterised and reveal that the PS integrins have an essential role in the adhesion of different cell layers to each other. The PS integrins are especially required for the function of the cell-matrix-cell junctions, where the muscles attach to the epidermis and where one surface of the developing wing adheres to the other. These junctions are similar to vertebrate focal adhesions and hemidesmosomes, which also contain integrins. Integrin-mediated cell to cell adhesion via the extracellular matrix provides a way for tissues to adhere to each other without intermingling of their cells.     

Integrins in cell migration

Integrin-based adhesion has served as a model for studying the central role of adhesion in migration. In this article, we outline modes of migration, both integrin-dependent and -independent in vitro and in vivo. We next discuss the roles of adhesion contacts as signaling centers and linkages between the ECM and actin that allows adhesions to serve as traction sites. This includes signaling complexes that regulate migration and the interplay among adhesion, signaling, and pliability of the substratum. Finally, we address mechanisms of adhesion assembly and disassembly and the role of adhesion in cellular polarity.     

Integrins in periodontal disease

Cell surface integrin receptors mediate cell adhesion, migration and cellular signaling in all nucleated cells. They are activated by binding to extracellular ligands or by intracellular proteins, such as kindlins that engage with their cytoplasmic tails. Cells in the periodontal tissues express several integrins with overlapping ligand-binding capabilities. A distinct phenotype in the periodontium has only been described for knockouts or mutations of three integrin subunits, α11, β6 and β2. Integrin α11β1 appears to have some regulatory function in the periodontal ligament of continuously erupting incisors in mice. Integrin αvβ6 is expressed in the junctional epithelium (JE) of the gingiva. Animals deficient in this receptor develop classical signs of periodontal disease, including inflammation, apical migration of the JE and bone loss, suggesting that it plays a role in the regulation of periodontal inflmmation, likely through activation of transforming growth factor-β1. Lack of integrin activation in the JE is also associated with periodontitis. Patients with kindlin-1 mutations have severe early-onset periodontal disease. Finally, patients with mutations in the leukocyte-specific β2 integrin subunit have severe periodontal problems due to lack of transiting neutrophils in the periodontal tissues.     

Integrins in mammary development

Integrins are ubiquitously expressed major cell surface receptors for extracellular matrix. Integrin interaction with their extracellular ligands triggers activation of the intracellular signaling pathways that control cell shape, motility, proliferation, survival, cell-type-specific gene expression. In this review, we summarize recent studies analyzing contribution of integrins to the control of the mammary morphogenesis and differentiation, function and maintenance of mammary stem and progenitor cells and resume the data from mouse models revealing the contribution of the integrin-mediated signaling to mammary tumorigenesis.