Integrins are a large family of transmembrane heterodimeric glycoproteins composed of α-and β-subunits that allow cells to attach to ECM constituents such as laminin and fibronectin, thus functionally and structurally linking the intracellular cytoskeleton with the outside world. Integrins also mediate cell-cell adhesive interactions. For instance, integrins on the surface of leukocytes are essential in mediating firm adhesion to and transmigration across the endothelium at sites of inflammation (Chapter 3), and they play a critical role in platelet aggregation (Chapter 4). Integrins attach to ECM components via a tripeptide arginine-glycine-aspartic acid motif (abbreviated RGD). In addition to providing focal attachment to underlying substrates, binding through the integrin receptors can also trigger signaling cascades that influence cell locomotion, proliferation, shape, and differentiation (
Fig. 1.16
Cell proliferation is fundamental to development, maintenance of steady-state tissue homeostasis, and replacement of dead or damaged cells. The key elements of cellular proliferation are accurate DNA replication accompanied by the coordinated synthesis of all other cellular constituents, followed by equal apportionment of DNA and other cellular constituents (e.g., organelles) to daughter cells through mitosis and cytokinesis.
The sequence of events that results in cell division is called the cell cycle. The cell cycle consists of G1 (pre-synthetic growth), S (DNA synthesis), G2 (premitotic growth), and M (mitotic) phases; quiescent cells that are not actively cycling are in the G0 state. (
Fig. 1.17 ). Cells can enter G1 either from the G0 quiescent cell pool or after completing a round of mitosis. Each stage requires completion of the previous step, as well as activation of necessary factors (see later); nonfidelity of DNA replication or cofactor deficiency results in arrest at the various transition points.
Fig. 1.17 Cell-cyclelandmarks.Thefigureshowsthecell-cyclephases(G0,G1,G2,S,andM),thelocationoftheG1restrictionpoint,andtheG1/SandG2/Mcell-cyclecheckpoints.G1restrictionpointreferstothephaseinG1atwhichthecellgetscommittedtothecellcyclewithoutfurtherneedofthegrowthfactorthatinitiatedcelldivision.Cellsfromlabiletissuessuchastheepidermisandthegastrointestinaltractmaycyclecontinuously;stablecellssuchashepatocytesarequiescentbutcanenterthecellcycle;permanentcellssuchasneuronsandcardiacmyocyteshavelostthecapacitytoproliferate.(Modified from Pollard TD, Earnshaw WC: Cellbiology,Philadelphia, 2002, Saunders.)
The cell cycle is regulated by numerous activators and inhibitors. Cell-cycle progression is driven by proteins called cyclins—named for the cyclic nature of their production and degradation—and cyclin-associated enzymes called cyclin-dependent kinases (CDKs) (
Fig. 1.18 ). CDKs acquire the ability to phosphorylate protein substrates (i.e., kinase activity) by forming complexes with the relevant cyclins. Transiently increased synthesis of a particular cyclin leads to increased kinase activity of the appropriate CDK binding partner; as the CDK completes its round of phosphorylation, the associated cyclin is degraded and the CDK activity abates. Thus, as cyclin levels rise and fall, the activity of associated CDKs likewise waxes and wanes.
More than 15 cyclins have been identified; cyclins D, E, A, and B appear sequentially during the cell cycle and bind to one or more CDKs. The cell cycle thus resembles a relay race in which each leg is regulated by a distinct set of cyclins: as one collection of cyclins leaves the track, the next set takes over.