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Conversely, changes inthe internal state of a cell must be able to trigger the making or breaking ofattachments. Thus there is a complex cross-talk between the adhesion machinery and chemical signaling pathways. We have described, for example, howchanges in pl2O-catenin may regulate the formation of adherensjunctions, andseveral intracellular signaling pathways can control junction formation by phosphorylating this and other junctional proteins.
Later, we shall discuss how themaking and breaking of adhesions can send signals into the cell interior throughmechanisms involving scaffold proteins on the intracellular side of the junction.Another of the central players in the two-way interaction between adhesionand signaling is thought to be B-catenin.
In this chapter, we have mentioned itas an essential intracellular anchor protein at adherens junctions, Iinking cadherins to actin filaments. In Chapter 15,we encountered it in another guise, as acomponent of the Wnt cell-cell signaling pathway, moving from the cytoplasmto the nucleus to activate the transcription oftarget genes.Separateparts ofthemolecule are responsible for the adhesiveand gene-regulatory functions, but anindividual molecule cannot do both things at once. Disintegration of anadherensjunction can set P-catenin molecules free to move from the cell surfaceinto the nucleus as signaling molecules, and, conversely,the activities of components of theWnt signaling pathway (which regulate the phosphorylation anddegradation of B-catenin) may control the availability of B-catenin to formadherens junctions.Some nonclassical cadherins transmit signals into the cell interior in yetother ways.
Members of the Flamingo subfamily, for example, have a seven-passtransmembrane domain suggestingthat they might function as G-protein-coupled receptors. Vascular endothelial cadherin (VE-cadherin) provides anotherexample.This protein not only mediates adhesion between endothelial cells butalso is required for endothelial cell survival. Although endothelial cells that donot expressVE-cadherin still adhere to one another via N-cadherin, they fail tosurvive, because they are unable to respond to an extracellular protein calleduascular endothelial gowth factor (WGF) that acts as a survival signal. VEGFbinds to a receptor tyrosine kinase (discussedin Chapter 15) that requires VEcadherin as a co-receptor.in theCell-CellAdhesionsMediateTransientSelectinsBloodstreamThe cadherin superfamily is central to cell-cell adhesion in animals, but at leastthree other superfamilies of cell-cell adhesion proteins are also important: theintegrins,the selectins,and the adhesive immunoglobulin(l)-superfamilymembers.
We shall discuss integrins in more detail later: their main function is incell-matrix adhesion, but a few of them mediate cell-cell adhesion in specializedcircumstances.Ca2*dependence provides one simple way to distinguish amongthese classesof proteins experimentally. Selectins,like cadherins and integrins,require Caz* for their adhesive function; Ig-superfamily members do not.Selectins are cell-surface carbohydrate-binding proteins AeUins)thatmediate a variety of transient, cell-cell adhesion interactions in the bloodstream.Their main role, in vertebrates at least, is in inflammatory responsesand in governing the traffic of white blood cells.'Whiteblood cells lead a nomadic life, roving between the bloodstream and the tissues,and this necessitatesspecial adhesive behavior.
The selectins control the binding of white blood cells to theendothelial cells lining blood vessels,thereby enabling the blood cells to migrateout of the bloodstream into a tissue.Each selectin is a transmembrane protein with a conserved lectin domainthat binds to a specific oligosaccharideon another cell (Figure l9-l9A). There areat least three types: L-selectinon white blood cells, P-selectinon blood plateletsand on endothelial cells that have been locally activated by an inflammatory11451146chapter19:cell Junctions,cell Adhesion,and the ExtracellurarMatrix-=-/lectin domainE G F - l i kdeo m a i nDasat ..--l am i n aP-selectinW E A KA D H E S I O NAND ROLLING(selectin-dependent)STRONGADHESIONAND EMIGRATION(integrin-dependent)bloodvesselwhite bloodcellCYTOSOLVendothelialcell(B)ussueaclrnf ilamentresponse, and E-selectln on activated endothelial cells.
In a lymphoid organ,such as a lymph node or a tonsil, the endothelial cells expressoligosaccharidesthat are recognized by L-selectin on lymphocytes, causing the lymphocytes toloiter and become trapped. At sites of inflammation, the roles are reversed:theendothelial cells switch on expression of selectins that recognize the oligosaccharides on white blood cells and platelets, flagging the cells dornrrto help dealwith the local emergency.Selectinsdo not act alone, however; they collaboratewith integrins, which strengthen the binding of the blood cells to the endothelium. The cell-cell adhesions mediated by both selectins and integrin s are heterophilic-that is, the binding is to a molecule of a different type: selectinsbindto specific oligosaccharides on glycoproteins and glycolipids, while integrinsbind to other specific proteins.Selectins and integrins act in sequence to let white blood cells leave thebloodstream and enter tissues (Figure l9-lgB).
The selectins mediate a weakadhesion because the binding of the lectin domain of the selectin to its carbohydrate ligand is of low affinity. This allows the white blood cell to adhere weaklyand reversibly to the endothelium, rolling along the surface of the blood ,r"rsei,propelled by the flow of blood. The rolling continues until the blood cell activates its integrins. As we discuss later, these transmembrane molecules can beswitched into an adhesive conformation that enables them to latch onto othermolecules external to the cell-in the present case,proteins on the surfaces ofthe endothelial cells. once it has attached in this way, the white blood cellescapesfrom the blood stream into the tissue by crawling out of the blood vessel between adjacent endothelial cells.Membersof the lmmunoglobulinSuperfamilyof proteinsMediateCa2+-lndependentCell-CellAdhesionThe chief endothelial cell proteins that are recognized by the white blood cellintegrins are called ICAMs (intercellular cell adhesion moleculeg or vcAMs fuas-Figure I 9-1 9 The structureand function ofselectins.(A)The structureof P-selectin.Theselectinattachesto the actincytoskeletonthroughanchorproteinsthat arestillpoorly(B)How selectinscharacterized.andintegrinsmediatethe cell-celladhesionsrequiredfor a white bloodcellto migrateout of the bloodstreaminto a tissue.First,selectinson endothelialcellsbind tooligosaccharideson the white bloodcell,sothat it becomeslooselyattachedto thevesselwall.Thenthe white bloodcellactivatesan integrin(usuallyone calledLFAl)in its plasmamembrane,enablingthisintegrinto bind to a proteincalledlCAM1,belongingto the immunoglobulinsuperfamily,in the membraneof theendothelialcell.Thiscreatesa strongerattachmentthat allowsthe white bloodcellto crawl out of the vessel.1147CADHERINSAND CELL_CELLADHESIONFigure19-20Two membersof the lg superfamilyof cell-celladhesionmolecules.NCAMis expressedon neuronsand manyothercelltypes,and:;:#ffon[5ffixlxT:[:il:i:lffillffi"".1']l!:iii.',",:::,Tffiadhesion.ICAMisexpressedcovalentlyattachedto it,hinderingto anendothelialcellsandsomeothercelltypesandbindsheterophilicallyintegrinon whitebloodcells.lg-likedomainsacid units).
By virtue of their negative charge,the long polysialic acid chains caninterfere with cell adhesion (because like charges repel one another); NCAMheavily loaded with sialic acid may even serve to inhibit adhesion, rather thancause it.A cell of a given type generallyuses an assortment of different adhesion proteins to interact with other cells,just as each cell uses an assortment of differentreceptors to respond to the many soluble extracellular signal molecules, such ashormones and growth factors, in its environment. Although cadherins and Igfamily members are frequently expressedon the same cells,the adhesionsmediated by cadherins are much stronger,and they are largely responsiblefor holdingcells together, segregatingcell collectives into discrete tissues,and maintainingtissue integrity.
Molecules such as NCAM seem to contribute more to the finetuning of these adhesive interactions during development and regeneration,playing a part in various specializedadhesivephenomena, such as that discussedfor blood and endothelial cells.Thus, while mutant mice that lack N-cadherin dieearly in development, those that lack NCAM develop relatively normally butshow some mild abnormalities in the development of certain specific tissues,including parts of the nervous system.to CreateaAct in ParallelManyTypesof CellAdhesionMoleculesSynapseCells of the nervous system, especially, rely on complex systems of adhesionmolecules, as well as chemotaxis and soluble signal factors, to guide axon outgrowth along precise pathways and to direct the formation of specific nerve connections (discussed in Chapter 22).
Adhesion proteins of the Ig superfamily,along with many other classesof adhesion and signaling molecules, have important roles in these processes.Thus, for example, in flies with a mutation of Fasciclin2, related to NCAM, some €xons follow aberrant pathways and fail to reachtheir proper targets.Another member of the Ig superfamily, Fasciclin3, enables the neuronalgrowth cones to recognize their proper targets when they meet them.
This protein is expressedtransiently on some motor neurons in Drosophila, as well as onthe muscle cells they normally innervate. If Fasciclin3 is genetically removedfrom these motor neurons, they fail to recognize their muscle targets and do notmake slmapseswith them. Conversely,if motor neurons that normally do notexpressFasciclin3 are made to expressthis protein, they will synapsewith Fasciclin3-expressing muscle cells to which they normally do not connect' It seemsthat Fasciclin3 mediates these synaptic connections by a homophilic "matchmaking" mechanism.
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