Lodish H. - Molecular Cell Biology (5ed, Freeman, 2003) (794361), страница 96
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The 41 integrin, which is foundon many hematopoietic cells (precursors of red and whiteblood cells), offers an example of this regulatory mechanism.For these hematopoietic cells to proliferate and differentiate, they must be attached to fibronectin synthesized by supportive (“stromal”) cells in the bone marrow. The 41integrin on hematopoietic cells binds to a Glu-Ile-Leu-AspVal (EILDV) sequence in fibronectin, thereby anchoring thecells to the matrix.
This integrin also binds to a sequence in aCAM called vascular CAM-1 (VCAM-1), which is presenton stromal cells of the bone marrow. Thus hematopoieticcells directly contact the stromal cells, as well as attach to thematrix. Late in their differentiation, hematopoietic cells decrease their expression of 41 integrin; the resulting reduction in the number of 41 integrin molecules on the cellsurface is thought to allow mature blood cells to detach fromthe matrix and stromal cells in the bone marrow and subsequently enter the circulation.Molecular Connections Between the ECMand Cytoskeleton Are Defectivein Muscular DystrophyThe importance of the adhesion receptor–mediatedlinkage between ECM components and the cytoskeleton is highlighted by a set of hereditarymuscle-wasting diseases, collectively called muscular dystrophies.
Duchenne muscular dystrophy (DMD), the most common type, is a sex-linked disorder, affecting 1 in 3300 boys,that results in cardiac or respiratory failure in the late teensor early twenties. The first clue to understanding the molecular basis of this disease came from the discovery that persons with DMD carry mutations in the gene encoding aprotein named dystrophin. This very large protein was foundto be a cytosolic adapter protein, binding to actin filamentsand to an adhesion receptor called dystroglycan. ❚Dystroglycan is synthesized as a large glycoprotein precursor that is proteolytically cleaved into two subunits. The subunit is a peripheral membrane protein, and the subunit is a transmembrane protein whose extracellular domainassociates with the subunit (Figure 6-29).
Multiple Olinked oligosaccharides are attached covalently to side-chainhydroxyl groups of serine and threonine residues in the subunit. These O-linked oligosaccharides bind to variousbasal lamina components, including the multiadhesive matrix protein laminin and the proteoglycans perlecan andAgrinNeurexinLamininPerlecanBasal laminaα,β-DystroglycanαO-linked sugarSarcoglycan complexN-linked sugarSarcospanγα β δβGRB2CytosolinrophDystSyntrophinsNOSActinα-Dystrobrevin▲ FIGURE 6-29 Schematic model of the dystrophinglycoprotein complex (DGC) in skeletal muscle cells.
TheDGC comprises three subcomplexes: the , dystroglycansubcomplex; the sarcoglycan/sarcospan subcomplex of integralmembrane proteins; and the cytosolic adapter subcomplexcomprising dystrophin, other adapter proteins, and signalingmolecules.
Through its O-linked sugars, -dystroglycan binds tocomponents of the basal lamina, such as laminin. Dystrophin—the protein defective in Duchenne muscular dystrophy—links-dystroglycan to the actin cytoskeleton, and -dystrobrevinlinks dystrophin to the sarcoglycan/sarcospan subcomplex. Nitricoxide synthase (NOS) produces nitric oxide, a gaseous signalingmolecule, and GRB2 is a component of signaling pathwaysactivated by certain cell-surface receptors (Chapter 14).
See textfor further discussion. [Adapted from S. J. Winder, 2001, TrendsBiochem. Sci. 26:118, and D. E. Michele and K. P. Campbell, 2003, J. Biol.Chem.]6.5 • Adhesive Interactions and Nonepithelial Cellsagrin. The neurexins, a family of adhesion molecules expressed by neurons, also are bound by the subunit.The transmembrane segment of the dystroglycan subunit associates with a complex of integral membrane proteins; its cytosolic domain binds dystrophin and otheradapter proteins, as well as various intracellular signalingproteins.
The resulting large, heterogeneous assemblage, thedystrophin glycoprotein complex (DGC), links the extracellular matrix to the cytoskeleton and signaling pathwayswithin muscle cells (see Figure 6-29). For instance, the signaling enzyme nitric oxide synthase (NOS) is associatedthrough syntrophin with the cytosolic dystrophin subcomplex in skeletal muscle. The rise in intracellular Ca2 duringmuscle contraction activates NOS to produce nitric oxide(NO), which diffuses into smooth muscle cells surroundingnearby blood vessels.
By a signaling pathway described inChapter 13, NO promotes smooth muscle relaxation, leading to a local rise in the flow of blood supplying nutrientsand oxygen to the skeletal muscle.Mutations in dystrophin, other DGC components,laminin, or enzymes that add the O-linked sugars to dystroglycan disrupt the DGC-mediated link between the exteriorand the interior of muscle cells and cause muscular dystrophies. In addition, dystroglycan mutations have been shownto greatly reduce the clustering of acetylcholine receptors onmuscle cells at the neuromuscular junctions (Chapter 7),which also is dependent on the basal lamina proteins lamininand agrin. These and possibly other effects of DGC defectsapparently lead to a cumulative weakening of the mechanicalstability of muscle cells as they undergo contraction and relaxation, resulting in deterioration of the cells and musculardystrophy.Ca2-Independent Cell–Cell Adhesion in Neuronaland Other Tissues Is Mediated by CAMsin the Immunoglobulin SuperfamilyNumerous transmembrane proteins characterized by thepresence of multiple immunoglobulin domains (repeats) intheir extracellular regions constitute the Ig superfamily ofCAMs, or IgCAMs.
The Ig domain is a common proteinmotif, containing 70–110 residues, that was first identified inantibodies, the antigen-binding immunoglobulins. Thehuman, D. melanogaster, and C. elegans genomes includeabout 765, 150, and 64 genes, respectively, that encode proteins containing Ig domains. Immunoglobin domains arefound in a wide variety of cell-surface proteins including Tcell receptors produced by lymphocytes and many proteinsthat take part in adhesive interactions.
Among the IgCAMsare neural CAMs; intercellular CAMs (ICAMs), which function in the movement of leukocytes into tissues; and junction adhesion molecules (JAMs), which are present in tightjunctions.As their name implies, neural CAMs are of particular importance in neural tissues. One type, the NCAMs, primarily227mediate homophilic interactions.
First expressed during morphogenesis, NCAMs play an important role in the differentiation of muscle, glial, and nerve cells. Their role in celladhesion has been directly demonstrated by the inhibitionof adhesion with anti-NCAM antibodies. Numerous NCAMisoforms, encoded by a single gene, are generated by alternative mRNA splicing and by differences in glycosylation.Other neural CAMs (e.g., L1-CAM) are encoded by differentgenes.
In humans, mutations in different parts of theL1-CAM gene cause various neuropathologies (e.g., mentalretardation, congenital hydrocephalus, and spasticity).An NCAM comprises an extracellular region with five Igrepeats and two fibronectin type III repeats, a single membrane-spanning segment, and a cytosolic segment that interacts with the cytoskeleton (see Figure 6-2). In contrast, theextracellular region of L1-CAM has six Ig repeats and four fibronectin type III repeats. As with cadherins, cis (intracellular)interactions and trans (intercellular) interactions probably playkey roles in IgCAM-mediated adhesion (see Figure 6-3).The covalent attachment of multiple chains of sialic acid,a negatively charged sugar derivative, to NCAMs alters theiradhesive properties.
In embryonic tissues such as brain, polysialic acid constitutes as much as 25 percent of the mass ofNCAMs. Possibly because of repulsion between the manynegatively charged sugars in these NCAMs, cell–cell contactsare fairly transient, being made and then broken, a propertynecessary for the development of the nervous system. In contrast, NCAMs from adult tissues contain only one-third asmuch sialic acid, permitting more stable adhesions.Movement of Leukocytes into Tissues Dependson a Precise Sequence of Combinatorially DiverseSets of Adhesive InteractionsIn adult organisms, several types of white blood cells (leukocytes) participate in the defense against infection caused byforeign invaders (e.g., bacteria and viruses) and tissue damage due to trauma or inflammation.
To fight infection andclear away damaged tissue, these cells must move rapidlyfrom the blood, where they circulate as unattached, relativelyquiescent cells, into the underlying tissue at sites of infection,inflammation, or damage. We know a great deal about themovement into tissue, termed extravasation, of four typesof leukocytes: neutrophils, which release several antibacterial proteins; monocytes, the precursors of macrophages,which can engulf and destroy foreign particles; and T and Blymphocytes, the antigen-recognizing cells of the immunesystem.Extravasation requires the successive formation andbreakage of cell–cell contacts between leukocytes in theblood and endothelial cells lining the vessels.
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