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Review
. 2011 Feb 1;3(2):a005116.
doi: 10.1101/cshperspect.a005116.

Genetic analyses of integrin signaling

Affiliations
Review

Genetic analyses of integrin signaling

Sara A Wickström et al. Cold Spring Harb Perspect Biol. .

Abstract

The development of multicellular organisms, as well as maintenance of organ architecture and function, requires robust regulation of cell fates. This is in part achieved by conserved signaling pathways through which cells process extracellular information and translate this information into changes in proliferation, differentiation, migration, and cell shape. Gene deletion studies in higher eukaryotes have assigned critical roles for components of the extracellular matrix (ECM) and their cellular receptors in a vast number of developmental processes, indicating that a large proportion of this signaling is regulated by cell-ECM interactions. In addition, genetic alterations in components of this signaling axis play causative roles in several human diseases. This review will discuss what genetic analyses in mice and lower organisms have taught us about adhesion signaling in development and disease.

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Figures

Figure 1.
Figure 1.
Molecular architecture of type I hemidesmosomes. Schematic depiction of a type I hemidesmosome found in stratified epithelia such as in basal skin keratinocytes. The core component is α6β4 integrin, which binds the basement membrane (BM) component laminin (LM)-322. α6β4 integrin recruits the plakin protein plectin through multiple interactions with the β4 integrin cytoplasmic tail, which initiates the formation of hemidesmosomes. This is followed by the recruitment of collagen XVII, which interacts both with β4 integrin and plectin as well as with LM 322. Collagen XVII in turn mediates the recruitment of another plakin, bullous pemphigoid antigen 230 (BP 230), which together with plectin provides the connection to intermediate filaments (IF). This linkage is essential to stabilize the hemidesmosome and to provide stable adhesion of the basal keratinocyte to the BM. Also, the transmembrane protein tetraspanin CD151 that interacts with α6 integrin is found in type I hemidesmosomes. Phosphorylation of serines (S) 1356, 1360, and 1364 on the cytoplasmic tail of β4 integrin by growth factors induces disassembly of hemidesmosomes, which promotes cell migration and signaling. The molecules are not drawn to scale.
Figure 2.
Figure 2.
Developmental functions of fibronectin-integrin interactions. Fibronectin (FN) is a dimeric glycyoprotein consisting of type I, type II, and type III modular repeats. Dimerization is achieved by disulfide bonds mediated by the two cysteines (S) in the COOH-terminus of the protein. The binding domains and motifs for integrins, as well as mouse developmental functions reported to depend on the particular interaction are indicated. Integrins that have been shown to mediate FN fibrillogenesis in vitro are marked by gray boxes.
Figure 3.
Figure 3.
Talin and kindlin regulate bidirectional integrin signaling. Bidirectional integrin signaling is essential for platelets (tan) to seal the injured blood vessel endothelium (red) and stop bleeding. Integrins in circulating, resting platelets exist in a low affinity state indicated by a bent confirmation (1). Following vessel injury, von Willebrand factor (vWF) and collagen are exposed to bind their receptors GPIb and GPVI that are expressed on the surface of platelets. Together with locally produced thrombin these receptors trigger the activation of αIIbβ3 integrin. This is achieved by promoting the association of talin-1 and kindlin-3 with the cytoplasmic tail of β3 integrin, facilitating a conformational change in the integrin (inside-out signaling) (2). The conformational change allows integrins to bind fibrinogen, vWF, and fibronectin with high affinity. As a result, platelets adhere to the vessel wall. Integrin ligation subsequently initiates signaling through kindlin and talin (outside-in signaling) (3) resulting in the recruitment of adaptor proteins and rearrangement of the cytoskeleton to promote cell spreading (4). This, together with integrin-mediated binding of soluble fibrinogen, results in platelet aggregation and formation of a stable clot (5). The molecules are not drawn to scale.

References

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