Structure of integrin, a glycoprotein involved in the transmembrane linkage between fibronectin and actin

Tamkun, John W.; DeSimone, Douglas W.; Fonda, D.; Patel, Ramila; Buck, Clayton A.; Horwitz, Alan F.; Hynes, Richard O.

doi:10.1016/0092-8674(86)90744-0

Cited by 791 publications

(460 citation statements)

References 84 publications

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“…Initially recognized as simple ECM-binding proteins, 36 integrins are now appreciated to elicit several cell signaling events. The canonical integrin-activated signaling pathway involves activation of an apical nonreceptor tyrosine kinase such as FAK 37 or a Src-family kinase, 38 which in turn promote activation of small GTPases of the Ras and Rho families, leading to the downstream activation of MAPK (mitogenactivated proteins kinase) cascades 39 ( Figure 1).…”

Section: General Signaling Events Initiated By Integrinsmentioning

confidence: 99%

Integrins as a distinct subtype of dependence receptors

Stupack

2005

Cell Death Differ

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In the absence of their cognate ligand, dependence receptors trigger programmed cell death. This function is the defining feature of dependence receptors, which include members of several different protein families. The integrins are a family of heterodimeric receptors for extracellular matrix (ECM) proteins, mediating cell anchorage and migration. Integrins share characteristics with dependence receptors, and integrin binding to substrate ECM ligands is essential for cell survival. Although integrins do not conform in all characteristics to the established definitions of dependence receptors, alterations in the expression of integrins and their ligands during physiological and pathological events, such as wound healing, angiogenesis and tumorigenesis, do regulate cell fate in a ligand-dependent manner. This biosensory function of integrins fits well with our current concept of dependence receptor action, and thus integrins may rightly be considered to comprise a distinct subclass of dependence receptor.

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Section: General Signaling Events Initiated By Integrinsmentioning

confidence: 99%

Integrins as a distinct subtype of dependence receptors

Stupack

2005

Cell Death Differ

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“…The first integrin was identified in 1986, when a complex, fibronectin-binding, membrane glycoprotein that was integral in linking the cytoskeleton with the extracellular matrix was identified 1 . Following this initial discovery, it soon became clear that this glycoprotein was only one member of a diverse family of receptors exhibiting similar functions, all of which are heterodimers composed of an α and a β subunit (FIG.…”

Section: Introductionmentioning

confidence: 99%

Integrins as therapeutic targets: lessons and opportunities

Cox

Brennan

Moran

2010

Nat Rev Drug Discov

413

350

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“…Integrins, large membrane-spanning heterodimeric proteins, were so named for their ability to link the extracellular and intracellular skeletons [Tamkun et al, 1986]. As an important class of cell adhesion receptors they participate in a wide-range of biological interactions, including development, tissue repair, angiogenesis, inflammation and hemostasis [Horwitz & Webb, 2003].…”

Section: Introductionmentioning

confidence: 99%

Integrin activation—the importance of a positive feedback

Iber¹,

Campbell

2006

Bull. Math. Biol.

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1Integrins mediate cell adhesion and are essential receptors for the development and functioning of multicellular organisms. Integrin activation is known to require both ligand and talin binding and to correlate with cluster formation but the activation mechanism and precise roles of these processes are not yet resolved. Here mathematical modeling, with known experimental parameters, is used to show that the binding of a stabilizing factor, such as talin, is alone insufficient to enable ligand-dependent integrin activation for all observed conditions; an additional positive feedback is required.Keywords Talin, integrin, receptor activation, Master equation, positive feedback 2 IntroductionIntegrins, large membrane-spanning heterodimeric proteins, were so named for their ability to link the extracellular and intracellular skeletons [Tamkun et al., 1986]. As an important class of cell adhesion receptors they participate in a wide-range of biological interactions, including development, tissue repair, angiogenesis, inflammation and hemostasis [Horwitz & Webb, 2003]. Cell adhesion and detachment as well as controlled actin polymerisation inside the cell are of particular importance in cell migration. The speed of cell movement depends on the density of integrins and ligands as well as their affinity of binding [Palecek et al., 1997]. Integrins are key components of focal adhesions, dynamic multi-protein complexes that are involved in the regulation of cell adhesion and migration. Focal adhesions [Zamir & Geiger, 2001] provide a physical link between integrins and the actin cytoskeleton as well as sites for signal transduction into the cell interior. Information about identified interactions and players in these complexes is ever-increasing but our overall understanding of how the ensemble works remains relatively poor.According to the current model of integrin activation, ligand binding shifts the equilibrium between different integrin conformations to the active one [Hynes, 2002]. The two extreme conformations of this allosteric protein are a bent or 'closed' conformation which represents the low affinity state for ligand and an 'open' conformation that will bind with high affinity to ligand. Conformational changes in the extracellular domain affect the cytoplasmic tails, which are separated in the open conformation but not in the closed. Separation of the cytoplasmic domains promotes their interaction with cytoskeletal and signal transduction molecules, and thus the activation of integrins and downstream signaling. The conformational equilibrium can be influenced both by ligand binding to the extracellular domain (outside-in signaling) and by binding of cytoplasmic proteins to the separated cytoplasmic domains (inside-out signaling). As well as changes in affinity induced by structural changes, integrins can also modulate their avidity by clustering, thus changing the valency of their interactions with ligand [Carman & Springer, 2003].Previous theoretical studies have addressed the mechanism of integrin clustering...

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Structure of integrin, a glycoprotein involved in the transmembrane linkage between fibronectin and actin

Cited by 791 publications

References 84 publications

Integrins as a distinct subtype of dependence receptors

Integrins as a distinct subtype of dependence receptors

Integrins as therapeutic targets: lessons and opportunities

Integrin activation—the importance of a positive feedback

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