Synergistic Roles for Receptor Occupancy and Aggregation in Integrin Transmembrane Function

Miyamoto, Shingo; Akiyama, Steven K.; Yamada, Kenneth M.

doi:10.1126/science.7846531

Cited by 825 publications

(593 citation statements)

References 26 publications

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“…[9,129,[216][217][218] In this way, a study addressing the mechanism by which T cell responses are enhanced by the co-receptor CD28 was undertaken. [87] Ligand binding to the TCR is necessary and sufficient for activation of T cells; however, co-stimulation of CD28 yields a more potent response.…”

Section: 1b G-protein Coupled Receptors (Gpcrs)-gpcrsmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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Cell surface receptors acquire information from the extracellular environment and coordinate intracellular responses. Evidence from biochemical and structural studies indicates that many receptors do not operate as individual entities, but rather as part of higher-order complexes (e.g. dimers and oligomers). Coupling the functions of multiple receptors may endow signaling pathways with the sensitivity and malleability required to govern cellular responses. Moreover, multireceptor signaling complexes may provide a means of spatially segregating otherwise degenerate signaling cascades. Despite the proposed importance of receptor-receptor processes in cellular signaling, questions concerning the mechanisms, extent, and consequences of receptor co-localization and interreceptor communication remain unanswered.Chemical synthesis can provide a variety of compounds with which to address the role of receptor assembly in signal transduction. The focus of this review is one such approach -the use of synthetic multivalent ligands to characterize receptor function. Multivalent ligands can be generated that possess a variety of sizes, shapes, valencies, orientations, and densities of binding elements. Their unique architectures imbue multivalent ligands with the ability to access binding modes not available to monovalent compounds. Multivalent ligands, therefore, are capable of illuminating aspects of inter-receptor processes that are not readily probed using conventional approaches. We suggest that, as focus shifts from investigations of the function of individual proteins and toward the analysis of multi-receptor signaling complexes, multivalent ligands will become even more valuable tools with which to ask sophisticated mechanistic questions. Further, multivalent ligands may provide new opportunities for manipulating receptor systems for the deconvolution of pathways, diagnosis, and, ultimately, the treatment of disease.

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Section: 1b G-protein Coupled Receptors (Gpcrs)-gpcrsmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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“…Dimerization is a well-known mechanism for activation of receptor kinases [62]. Intramembrane clustering has also been shown to be important for activation of downstream activities of non-catalytic receptors [63,64] and cell-adhesion molecules [65][66][67][68].…”

Section: Core-protein-mediated Oligomerizationmentioning

confidence: 99%

“…Integrin receptors bind talin [133] and α-actinin [134] and other cytoskeleton-associated proteins [65,68,117], selectins bind α-actinin [135], and cadherins bind catenins [136]. In the case of integrin receptors it has been shown that one of the elements that regulates cytoskeleton association is clustering of the receptors within the plane of the membrane [65].…”

Section: Syndecan-cytoskeleton Associationmentioning

confidence: 99%

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Syndecans: multifunctional cell-surface co-receptors

Carey

1997

Biochemical Journal

621

497

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This review will summarize our current state of knowledge of the structure, biochemical properties and functions of syndecans, a family of transmembrane heparan sulphate proteoglycans. Syndecans bind a variety of extracellular ligands via their covalently attached heparan sulphate chains. Syndecans have been proposed to play a role in a variety of cellular functions, including cell proliferation and cell–matrix and cell–cell adhesion. Syndecan expression is highly regulated and is cell-type- and developmental-stage-specific. The main function of syndecans appears to be to modulate the ligand-dependent activation of primary signalling receptors at the cell surface. Principal functions of the syndecan core proteins are to target the heparan sulphate chains to the appropriate plasma-membrane compartment and to interact with components of the actin-based cytoskeleton. Several functions of the syndecans, including syndecan oligomerization and actin cytoskeleton association, have been localized to specific structural domains of syndecan core proteins.

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“…A prominent example is the transport of oosperm from ovary to uterus through the fallopian tube during pregnancy. While it is clear that the transport of oosperm involves smooth muscle contraction [1,2], the detailed mechanism still remains elusive [1][2][3][4][5][6][7], due in part to the complexity of cellsubstrate interactions via receptor-ligand binding as well as various physical forces inside and outside of the cytoskeleton [8][9][10][11][12]. Cells are known to respond to mechanical forces exerted through surrounding fluid, adhering beads or substrates [9,[12][13][14], and they could detach, slip or roll on a substrate in response to these forces [15][16][17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%