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C H A P T E R 12

CELL ADHESION

Rodger P. McEver and Francis W. Luscinskas

Cell adhesion is essential for the development and maintenance of signaling. The principal constituents of the ECM are adhesive
multicellular organisms. Cell-to-cell and cell-to-matrix adhesion proteins and proteoglycans. The major proteins are collagens, von
provide a mechanism for intercellular communication and to define Willebrand factor (vWF), thrombospondin, elastin, fibronectin,
the three-dimensional architecture of organs. The regulated nature laminin, and vitronectin. These proteins are large and often highly
of cell adhesion is particularly evident in the hematopoietic system, extended, and consist of multiple domains with different binding
where blood cells routinely make transitions between nonadherent functions. In some proteins such as fibronectin, alternative splicing
and adherent phenotypes during differentiation, and in response to can increase diversity by producing molecules with variable numbers
stimuli in the circulation or extravascular space. of domains. In addition, stretching of fibronectin can expose cryptic
In the bone marrow (BM), hematopoietic stem cells reside in a binding sites. The many binding domains allow adhesive proteins to
specialized microenvironment called the stem cell niche, and their interact with each other as well as with cell-surface receptors, resulting
proliferation and differentiation are controlled not only by soluble in multipoint contacts that stabilize matrix structure. One adhesive
growth factors but also by adhesion to stromal cells and matrix protein, fibrinogen, is found predominantly in plasma but also may
molecules (see Chapter 9 for more detailed discussion). Weaken- be deposited in exposed subendothelial matrix after vascular injury.
ing of these adhesive interactions is required for mature blood cells Fibronectin, vitronectin, thrombospondin, and vWF are located
to enter the circulation. Circulating erythrocytes normally remain predominantly in the ECM but also are found in plasma in lower
nonadhesive until they become senescent and are finally cleared by amounts. Several adhesive proteins also are stored in α-granules of
the reticuloendothelial system (see Chapter 33 for more discussion). platelets, where they are secreted after platelet activation at sites of
Other circulating blood cells often participate in regulated adhesive vascular injury. Similarly, the endothelium stores adhesive proteins
events during their lifespan. For example, prothymocytes adhere to in cytoplasmic storage granules, called Weibel–Palade bodies, that are
thymic stromal cells where they undergo guided movement from released upon injury or activation.
the cortex to the medulla during maturation before reentering the Proteoglycans contain protein cores to which are covalently
circulation. T cells regularly stick to the specialized high endothelial attached many glycosaminoglycans—long linear polymers of
venules of lymphoid tissues, migrate into these tissues for sampling repeating disaccharides. Most proteoglycans are in the ECM, but
of processed antigens, and then exit via the lymphatics to recirculate some are anchored on cell surfaces through a core protein that
in the blood (see Chapter 13 for more discussion). During inflam- contains a membrane-spanning domain. Hyaluronan is a unique
mation, specific classes of leukocytes roll at very low velocity on the glycosaminoglycan that forms polymers with molecular masses up to
endothelium that line all blood vessels, then adhere more tightly, several million daltons that are not covalently attached to a protein.
and finally emigrate between endothelial cells into the tissues. There, Hyaluronan forms noncovalent interactions with globular domains
neutrophils and monocytes phagocytose invading pathogens, and on the protein core of proteoglycans and with a small molecule
lymphocytes adhere to antigen-presenting cells, such as dendritic called link protein. The resultant hyaluronan–proteoglycan complexes
cells, B cells, and macrophages (see Chapter 123 for more discus- can become very large, contributing to the structural stability of
sion). During hemorrhage, platelets stick to exposed subendothelial the matrix and function as space fillers during embryonic develop-
matrix components, spread, and recruit additional platelets into large ment. Hyaluronan can also bind to cell-surface receptors and is also
aggregates that serve as an efficient surface for thrombin and fibrin abundantly produced during wound healing.
generation. This is discussed in more detail later in Chapter 124.
Leukocytes also adhere to activated platelets and to other leukocytes,
and platelets roll on the endothelium. When activated, endothelial INTEGRINS
cells increase expression of molecules that affect the adhesiveness of
platelets or leukocytes. Tight contacts between adjacent endothelial Integrins are a broadly distributed group of cell-surface adhesion
cells also regulate access of blood cells to the underlying tissues. receptors that consist of noncovalently associated α- and β-subunits
(Fig. 12.1 and Table 12.1). There are 18 α-chains and eight β-chains
that pair in many, but not all, of the possible combinations. All blood
ADHESION MOLECULES cells have several different integrins. The four β2 integrins, each
paired with a unique α-subunit, are expressed only by leukocytes, and
Cells adhere through noncovalent bond formation between mac- the αIIbβ3 integrin (glycoprotein IIb–IIIa [GPIIb–IIIa]) is expressed
romolecules on cell surfaces with macromolecules on other cell only by megakaryocytes and platelets. Multidomain adhesive proteins
surfaces or in the extracellular matrix (ECM). These interactions of the ECM are ligands for many integrins. Integrins are unusual
involve either protein–protein or protein–carbohydrate recognition. adhesion molecules because they usually reside in an inactive state
Although some adhesion molecules are expressed only by blood or on the cell surface until they receive an activating signal. Some
endothelial cells, most also are synthesized by other cells. Many integrins bind to specific domains of several different proteins, and
adhesion molecules can be grouped into families according to related some adhesive proteins bind to several different integrins. These
structural and functional features. interactions generally mediate cell–matrix and cell–cell adhesion. A
unique feature of integrins is transmission of signals in both direc-
tions across the cell plasma membrane. Integrin binding to matrix
EXTRACELLULAR MATRIX PROTEINS informs the interior of the cell (outside-in), and intracellular signals
or conditions inside cells transmit signals outward (inside-out) that
The ECM provides structural and mechanical support for many regulate binding to matrix or to adhesion receptors on the surface
tissues and spatial cues that enable cell–cell communication and of adjacent cells. Force can also regulate integrin adhesive function.

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