Regulation of alpha 6 beta 1 integrin laminin receptor function by the cytoplasmic domain of the alpha 6 subunit.

Shaw, Leslie M.; Mercurio, Arthur M.

doi:10.1083/jcb.123.4.1017

Cited by 55 publications

(30 citation statements)

References 44 publications

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“…The a-integrin CT MD region is dispensable for talin binding but is required for talin-and kindlin-induced integrin conformational change. Our data explain to a certain extent the previous observations that deletion of the a-integrin CT MD region diminished cell adhesion mediated by a 1 , a 2 , a 4 , a V and a 6 integrins (Kassner and Hemler, 1993;Kawaguchi and Hemler, 1993;Shaw and Mercurio, 1993;Filardo and Cheresh, 1994;Kassner et al, 1994;Kawaguchi et al, 1994;Yauch et al, 1997;Abair et al, 2008) and that the a L CT MD deletion reduced the sensitivity of a L b 2 integrin to PMA stimulation (Lu and Springer, 1997). It is not readily known how the a-integrin CT MD region contributes to maintaining the resting state because current structural studies show diverse structures for the integrin cytoplasmic tails (supplementary material Fig.…”

Section: Icam-1 Binding (Nomalized Mfi)supporting

confidence: 78%

“…The same phenomenon was observed with a 2 integrin . However, deletion of the a CT MD region of a 1 , a 2 , a 4 , a V or a 6 integrin diminished cell adhesion (Kassner and Hemler, 1993;Kawaguchi and Hemler, 1993;Shaw and Mercurio, 1993;Filardo and Cheresh, 1994;Kassner et al, 1994;Kawaguchi et al, 1994;Yauch et al, 1997;Abair et al, 2008), indicating that there are different regulatory roles of a CT MD regions among different integrins.…”

Section: Icam-1 Binding (Nomalized Mfi)mentioning

confidence: 99%

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The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

Liu¹,

Wang²,

Thinn³

et al. 2015

Journal of Cell Science

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BSTRACTStudies on the mechanism of integrin inside-out activation have been focused on the role of b-integrin cytoplasmic tails, which are relatively conserved and bear binding sites for the intracellular activators including talin and kindlin. Cytoplasmic tails for a-integrins share a conserved GFFKR motif at the membrane-proximal region and this forms a specific interface with the b-integrin membraneproximal region to keep the integrin inactive. The a-integrin membrane-distal regions, after the GFFKR motif, are diverse both in length and sequence and their roles in integrin activation have not been well-defined. In this study, we report that the a-integrin cytoplasmic membrane-distal region contributes to maintaining integrin in the resting state and to integrin inside-out activation.Complete deletion of the a-integrin membrane-distal region diminished talin-and kindlin-mediated integrin ligand binding and conformational change. A proper length and suitable amino acids in a-integrin membrane-distal region was found to be important for integrin inside-out activation. Our data establish an essential role for the a-integrin cytoplasmic membrane-distal region in integrin activation and provide new insights into how talin and kindlin induce the high-affinity integrin conformation that is required for fully functional integrins.

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Section: Icam-1 Binding (Nomalized Mfi)supporting

confidence: 78%

Section: Icam-1 Binding (Nomalized Mfi)mentioning

confidence: 99%

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

Liu¹,

Wang²,

Thinn³

et al. 2015

Journal of Cell Science

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“…For this purpose, the ␣ 6A ␤ 1 and ␣ 6B ␤ 1 integrins were clustered on the surface of the P388D1 transfectants using the 2B7 mAb and a secondary Ab that recognizes 2B7. It is important to note that 2B7 recognizes the extracellular domain of the ␣ 6 subunit that is identical in the ␣ 6A ␤ 1 and ␣ 6B ␤ 1 integrins (21). Ligation of the ␣ 6A ␤ 1 integrin induced a more marked increase in the appearance of the phosphorylated form of ERK2 in comparison to ligation of ␣ 6B ␤ 1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of Mitogen-activated Protein Kinase Activation by the Cytoplasmic Domain of the α6 Integrin Subunit

Wei

Shaw

Mercurio

1998

Journal of Biological Chemistry

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We examined the possibility that the ␣ 6A and ␣ 6B cytoplasmic domain variants of the ␣ 6 ␤ 1 integrin differentially activate p42 and p44 mitogen-activated protein (MAP) kinases. P388D1 macrophages that express equivalent surface levels of either the ␣ 6A ␤ 1 or ␣ 6B ␤ 1 integrin were used to examine this issue. Adhesion to laminin-1 mediated by the ␣ 6A ␤ 1 integrin triggered activation of a substantial fraction of total p42 and p44 MAP kinases as assessed using a mobility shift assay, immunoblot analysis with a phosphospecific MAP kinase antibody, and an immune complex kinase assay. In contrast, ligation of the ␣ 6B ␤ 1 integrin did not trigger significant MAP kinase activation. These data were confirmed by antibody clustering of the ␣ 6 ␤ 1 integrins. Both the ␣ 6A ␤ 1 and ␣ 6B ␤ 1 integrins were capable of activating the p70 ribosomal S6 kinase and this activation, unlike MAP kinase activation, is dependent on phosphoinositide 3-OH kinase. Activation of MAP kinase by ␣ 6 ␤ 1 requires both Ras and protein kinase C activity. A functional correlate for differential activation of MAP kinase was provided by the findings that the ␣ 6A ␤ 1 transfectants migrated significantly better on laminin than the ␣ 6B ␤ 1 transfectants and this migration was dependent on MAP kinase activity based on the use of the MAP kinase kinase (MEK1) inhibitor PD98059. Our findings demonstrate that the ␣ 6 ␤ 1 integrin can activate MAP kinase, that this activation is regulated by the cytoplasmic domain of the ␣ 6 subunit, and that it relates to ␣ 6 ␤ 1 -mediated migration.The mechanisms by which integrins modulate the activity of the ERK1 1 and ERK2 members of the MAP kinase family are of interest because these kinases regulate cell growth (1-4) and have been implicated in other important functions such as cell migration (5). Initial studies demonstrated that MAP kinase could be activated by integrin-mediated attachment to the extracellular matrix (6 -8). More recently, the possible involvement of other signaling molecules including Ras and focal adhesion kinase (FAK) in MAP kinase activation by integrins has been explored, an area that remains controversial (9 -13). These studies, however, did not address the possibility that specificity exists among integrins for their ability to modulate MAP kinase activity. Recently, however, this possibility was substantiated by the finding that only a subset of integrins (␣ 1 ␤ 1 , ␣ 5 ␤ 1 , and ␣ v ␤ 3 ) can activate MAP kinase (14). The ability of these integrins to activate MAP kinase was found to be mediated by the recruitment and phosphorylation of Shc and to be specified by the membrane-proximal portion of the extracellular domain of the integrin ␣ subunit, its transmembrane segment, or both. Other integrins (␣ 2 ␤ 1 , ␣ 3 ␤ 1 , and ␣ 6 ␤ 1 ) were unable to induce MAP kinase activation in these assays (14).An issue that has not been resolved with respect to integrinmediated activation of MAP kinase is the possible role of the cytoplasmic domain of the integrin ␣ subunit in regulating this ac...

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“…Therefore, although several cytoplasmic proteins have been shown to bind to integrin ␣-subunits (Shattil and Ginsberg, 1997;Yamada and Geiger, 1997;Liu et al, 1999), the significance of binding of cytoskeletal proteins to the ␣-cytoplasmic domain has not always been obvious. A key observation is that, whereas the ␣-cytoplasmic domain seems to play a passive role in localization of integrins to focal contacts, it plays a more active role in some integrin-mediated cell functions, such as cell motility and collagen fibril formation (Kassner and Hemler, 1993;Kawaguchi and Hemler, 1993;Shaw and Mercurio, 1993;Filardo and Cheresh, 1994;Kassner et al, 1994). It was recently demonstrated that the integrin ␣ 4 -chain binds specifically to paxillin and that this binding correlates with increased cell migration, decreased spreading, and stress fiber and focal contact formation (Liu et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Activation-enhanced α_IIbβ₃-Integrin–Cytoskeleton Interactions Outside of Focal Contacts Require the α-Subunit

Kucik

O’Toole

Zheleznyak

et al. 2001

MBoC

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Integrins link the cell's cytoskeleton to the extracellular matrix, as well as to receptors on other cells. These links occur not only at focal contacts but also at smaller integrin-containing protein complexes outside of focal contacts. We previously demonstrated the importance of focal contactindependent integrin-cytoskeleton interactions of ␤ 2 integrins: activation of adhesion resulted from a release of integrins from cytoskeletal constraints. To determine whether changes in integrin-cytoskeleton interactions were related to activation of the integrin, we used single particle tracking to examine focal contact-independent cytoskeletal associations of ␣ IIb ␤ 3 -integrin, in which activation results in a large conformational change. Direct activation of ␣ IIb ␤ 3 by mutation did not mimic activation of lymphocytes with phorbol ester, because it enhanced integrin-cytoskeleton interactions, whereas activation of lymphocytes decreased them. Using additional integrin mutants, we found that both ␣-and ␤-cytoplasmic domains were required for these links. This suggests that 1) both ␤ 2 -and ␤ 3 -integrins interact with the cytoskeleton outside of focal contacts; 2) activation of a cell and activation of an integrin are distinct processes, and both can affect integrin-cytoskeleton interactions; and 3) the role of the ␣-subunit in integrin-cytoskeleton interactions in at least some circumstances is more direct than generally supposed.

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Regulation of alpha 6 beta 1 integrin laminin receptor function by the cytoplasmic domain of the alpha 6 subunit.

Abstract: Abstract. The tx6~l integrin is expressed on the macrophage surface in an inactive state and requires cellular activation with PMA or cytokines to function as a laminin receptor (Shaw, L. M., J. M. Messier, and A. M.

Cited by 55 publications

References 44 publications

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

Regulation of Mitogen-activated Protein Kinase Activation by the Cytoplasmic Domain of the α6 Integrin Subunit

Activation-enhanced α_IIbβ₃-Integrin–Cytoskeleton Interactions Outside of Focal Contacts Require the α-Subunit

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Regulation of alpha 6 beta 1 integrin laminin receptor function by the cytoplasmic domain of the alpha 6 subunit.

Abstract: Abstract. The tx6~l integrin is expressed on the macrophage surface in an inactive state and requires cellular activation with PMA or cytokines to function as a laminin receptor (Shaw, L. M., J. M. Messier, and A. M.

Cited by 55 publications

References 44 publications

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

Regulation of Mitogen-activated Protein Kinase Activation by the Cytoplasmic Domain of the α6 Integrin Subunit

Activation-enhanced αIIbβ3-Integrin–Cytoskeleton Interactions Outside of Focal Contacts Require the α-Subunit

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Activation-enhanced α_IIbβ₃-Integrin–Cytoskeleton Interactions Outside of Focal Contacts Require the α-Subunit