Modulation of the Affinity of Integrin α
 IIb
 β
 3
 (GPIIb-IIIa) by the Cytoplasmic Domain of α
 IIb

O’Toole, Timothy E.; Mandelman, David; Forsyth, Jane; Shattil, Sanford J.; Plow, Edward F.; Ginsberg, Mark H.

doi:10.1126/science.1948065

Cited by 323 publications

(206 citation statements)

References 26 publications

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“…Although not directly involved in trans interactions, intracellular domains of adhesion molecules have been shown to influence extracellular interactions, as seen with integrins (54,55). The role of the intracellular domains of the SALMs remains to be determined, but it is likely that they will be involved in functions related to intracellular signaling and forming associations with other proteins.…”

Section: Discussionmentioning

confidence: 99%

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Seabold

Wang

Chang

et al. 2008

Journal of Biological Chemistry

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Synaptic adhesion-like molecules (SALMs) are a newly discovered family of adhesion molecules that play roles in synapse formation and neurite outgrowth. The SALM family is comprised of five homologous molecules that are expressed largely in the central nervous system. SALMs 1-3 contain PDZ-binding domains, whereas SALMs 4 and 5 do not. We are interested in characterizing the interactions of the SALMs both among the individual members and with other binding partners. In the present study, we focused on the interactions formed by the five SALM members in rat brain and heterologous cells. In brain, we found that SALMs 1-3 strongly co-immunoprecipitated with each other, whereas SALMs 4 and 5 did not, suggesting that SALMs 4 and 5 mainly form homomeric complexes. In heterologous cells transfected with SALMs, co-immunoprecipitation studies showed that all five SALMs form heteromeric and homomeric complexes. We also determined if SALMs could form trans-cellular associations between transfected heterologous cells. Both SALMs 4 and 5 formed homophilic, but not heterophilic associations, whereas no trans associations were formed by the other SALMs. The ability of SALM4 to form trans interactions is due to its extracellular N terminus because chimeras of SALM4 N terminus and SALM2 C terminus can form trans interactions, whereas chimeras of SALM2 N terminus and SALM4 C terminus cannot. Co-culture experiments using HeLa cells and rat hippocampal neurons expressing the SALMs showed that SALM4 is recruited to points of contact between the cells. In neurons, these points of contact were seen in both axons and dendrites.Critical steps in the development of the nervous system, including cell migration, neurite outgrowth, growth cone guidance, and synapse formation, depend on cellular interactions mediated by adhesion molecules (1-4). A number of adhesion molecules that are essential to the proper development of the nervous system have been identified (5-7). The importance of these molecules is illustrated in cases of dysfunctional adhesion molecules that have been associated with specific disorders in humans, including SLITRK1 in Tourette syndrome (8) and neuroligin in autism (9, 10). Whereas our understanding of the role of adhesion molecules in neuronal development is rapidly increasing, little is known about their functions, and it is likely that many remain to be identified.Synaptic adhesion-like molecules (SALMs) 2 are a recently identified class of adhesion molecules that are highly enriched in brain (11-13). All five members of the SALM family contain extracellular leucine-rich repeats (LRR), an immunoglobulin C2-like (IgC2) domain, a fibronectin type III (FNIII) domain, a transmembrane domain, and a cytoplasmic C-terminal tail. SALMs 1-3 contain a C-terminal PDZ-binding domain (PDZ-BD), which associates with the PSD-95 family of proteins (11-13). SALMs are expressed early in the developing nervous system and persist into adulthood. They are present at the synaptic membrane as well as at non-synaptic locations. SALM1 overe...

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Section: Discussionmentioning

confidence: 99%

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Seabold

Wang

Chang

et al. 2008

Journal of Biological Chemistry

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“…However, we cannot rule out the possibility that the as intracellular domain plays a supportive or regulatory role in receptor distribution and function, or that it plays a more active role in receptor localization in other cell types. Interestingly, the al,b intracellular domain of the platelet receptor, «11nß3, functions in the regulation of ligand binding affinity, and the as intracellular domain cannot substitute for the «116 intracellular domain in this regulation (O'Toole et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Regulation of fibronectin receptor distribution [published erratum appears in J Cell Biol 1992 Jul;118(2):491]

LaFlamme

Akiyama

Yamada

1992

The Journal of Cell Biology

266

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Abstract. To determine the role of each intracellular domain of the fibronectin receptor in receptor distribution, chimeric receptors were constructed containing the human interleukin-2 receptor (gp55 subunit) as the extracellular and transmembrane domains, in combination with either the a5 or ß, intracellular domain of the fibronectin receptor as the cytoplasmic domain . These chimeric receptors were transiently expressed in normal fibroblasts, and their localization on the cell surface was determined by immunofluorescence using antibodies to the human interleukin-2 receptor. The a5 chimera was expressed diffusely on the plasma membrane . The 01 chimera, however, colocalized with the endogenous fibronectin receptor at focal contacts of cells spread on fibronectin . On cells spread in the presence of serum, the 01 chimera colocalized both with the fibronectin receptor at sites of extracellular fibronectin fibrils and with the vitronectin receptor at focal contacts. The 01 intracellular domain alone, therefore, contains sufficient information to target the chimeric receptor to regions of the cell where ligandoccupied integrin receptors are concentrated. The find-T HE integrins, a family of transmembrane heterodimeric receptors consisting of a and ß subunits, play a central role in cell adhesion and migration . These processes are important in development, wound healing, metastasis, and other biological events. Integrins function in both cell-cell and cell-substratum adhesion . Integrin heterodimers can be classified into subfamilies based on the different ß subunits. Different combinations of a and ß subunits give rise to receptors with different ligand specificities, including receptors for fibronectin, vitronectin, collagen, and laminin. Although some integrins are cell-type specific, most function in many cell types, and most cell types express a variety ofintegrin receptors, allowing them to interact with many extracellular matrix components (recent reviews include Akiyama et al

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“…The anti-␣ IIb ␤ 3 monoclonal antibodies PAC-1 and anti-LIBS6, the anti-␤ 3 C-terminal peptide antiserum 8275, and the ␣ IIb ␤-specific antagonist Ro43-5054 have been described previously (37)(38)(39). cDNAs encoding Tac-␣ 5 , Tac-␤ 3 , mouse talin F2F3 (residues 206 -305; SwissProt entry TALI_MOUSE (P26039)), ␣ IIb and ␤ 3 integrin tail model proteins, GFP-PIPKI␥-87, GFP-PIPKI␥-90, GFP-PIPKI␥-90(W647A), and GST-fibronectin, type III repeats 9 -11 (FN9 -11) have been described previously (26, 33, 40 -42).…”

Section: Methodsmentioning

confidence: 99%

“…(38). To test whether competition for talin also mediated the trans-dominant inhibition of more active integrins, we examined chimeric ␣ IIb ␤ 3 integrins.…”

Section: Isolated ␤ Tails Require An Intact Talin-binding Site To Medmentioning

confidence: 99%

Competition for Talin Results in Trans-dominant Inhibition of Integrin Activation

Calderwood

Tai

Paolo

et al. 2004

Journal of Biological Chemistry

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The ability of integrin adhesion receptors to undergo rapid changes in affinity for their extracellular ligands (integrin activation) is essential for the development and function of multicellular animals and is dependent on interactions between the integrin ␤ subunit-cytoplasmic tail and the cytoskeletal protein talin. Cross-talk among different integrins and between integrins and other receptors impacts many cellular processes including adhesion, spreading, migration, clot retraction, proliferation, and differentiation. One form of integrin cross-talk, transdominant inhibition of integrin activation, occurs when ligand binding to one integrin inhibits the activation of a second integrin. This may be relevant clinically in a number of settings such as during platelet adhesion, leukocyte trans-migration, and angiogenesis. Here we report that competition for talin underlies the trans-dominant inhibition of integrin activation. This conclusion is based on our observations that (i) ␤ tails selectively defective in talin binding are unable to mediate trans-dominant inhibition, (ii) trans-dominant inhibition can be reversed by overexpression of integrin binding and activating fragments of talin, and (iii) expression of another non-integrin talin-binding protein, phosphatidylinositol phosphate kinase type I␥-90, also inhibits integrin activation. Thus, the sequestration of talin by the suppressive species is both necessary and sufficient for trans-dominant inhibition of integrin activation.

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Modulation of the Affinity of Integrin α _IIb β ₃ (GPIIb-IIIa) by the Cytoplasmic Domain of α _IIb

Cited by 323 publications

References 26 publications

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Regulation of fibronectin receptor distribution [published erratum appears in J Cell Biol 1992 Jul;118(2):491]

Competition for Talin Results in Trans-dominant Inhibition of Integrin Activation

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Modulation of the Affinity of Integrin α IIb β 3 (GPIIb-IIIa) by the Cytoplasmic Domain of α IIb

Cited by 323 publications

References 26 publications

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Regulation of fibronectin receptor distribution [published erratum appears in J Cell Biol 1992 Jul;118(2):491]

Competition for Talin Results in Trans-dominant Inhibition of Integrin Activation

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Modulation of the Affinity of Integrin α _IIb β ₃ (GPIIb-IIIa) by the Cytoplasmic Domain of α _IIb