Dataset Information

An interaction between {alpha}v{beta}8 integrin and Band 4.1B via a highly conserved region of the Band 4.1 C-terminal domain.

ABSTRACT: alphavbeta8 Integrin is highly expressed in the vertebrate CNS, and mice lacking the alphav or beta8 genes develop cerebral hemorrhage due to defective interactions between blood vessels and alphavbeta8-expressing neural cells. Although alphavbeta8 binds many of the same extracellular matrix protein ligands as other integrins, very little is known about the intracellular signal transduction events used by alphavbeta8 to regulate CNS development. Here we identify Band 4.1B as an intracellular factor that interacts selectively with the beta8 cytoplasmic tail. The association with alphavbeta8 occurs via the band 4.1B C-terminal domain, a region highly conserved among the various Band 4.1 family members. Indeed, we show that beta8 integrin interacts directly with the C-terminal domains of several Band 4.1 proteins and colocalizes with them in cultured astrocytes and in the brain. These data identify a previously uncharacterized interaction between an integrin and Band 4.1 family members and suggest an important functional role for alphavbeta8-Band 4.1 interactions in the development and maintenance of the CNS.

SUBMITTER: McCarty JH

PROVIDER: S-EPMC1224645 | biostudies-literature | 2005 Sep

REPOSITORIES: biostudies-literature

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An interaction between {alpha}v{beta}8 integrin and Band 4.1B via a highly conserved region of the Band 4.1 C-terminal domain.

McCarty Joseph H JH Cook Aaron A AA Hynes Richard O RO

Proceedings of the National Academy of Sciences of the United States of America 20050912 38

alphavbeta8 Integrin is highly expressed in the vertebrate CNS, and mice lacking the alphav or beta8 genes develop cerebral hemorrhage due to defective interactions between blood vessels and alphavbeta8-expressing neural cells. Although alphavbeta8 binds many of the same extracellular matrix protein ligands as other integrins, very little is known about the intracellular signal transduction events used by alphavbeta8 to regulate CNS development. Here we identify Band 4.1B as an intracellular fac ...[more]

PMID: 16157875

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Project description:Integrin activation, the rapid conversion of integrin adhesion receptors from low to high affinity, occurs in response to intracellular signals that act on the short cytoplasmic tails of integrin beta subunits. Talin binding to integrin beta tails provides one key activation signal, but additional factors are likely to cooperate with talin to regulate integrin activation. The integrin beta tail-binding proteins kindlin-2 and kindlin-3 were recently identified as integrin co-activators. Here we report an analysis of kindlin-1 and kindlin-2 interactions with beta1 and beta3 integrin tails and describe the effect of kindlin expression on integrin activation. We demonstrate a direct interaction of kindlin-1 and -2 with recombinant integrin beta tails in pulldown binding assays. Our mutational analysis shows that the second conserved NXXY motif (Tyr(795)), a preceding threonine-containing region (Thr(788) and Thr(789)) of the integrin beta1A tail, and a conserved tryptophan in the F3 subdomain of the kindlin FERM domain (kindlin-1 Trp(612) and kindlin-2 Trp(615)) are required for direct kindlin-integrin interactions. Similar interactions were observed for integrin beta3 tails. Using fluorescence-activated cell sorting we further show that transient expression of kindlin-1 or -2 in Chinese hamster ovary cells inhibits the activation of endogenous alpha5beta1 or stably expressed alphaIIbbeta3 integrins. This inhibition is not dependent on direct kindlin-integrin interactions because mutant kindlins exhibiting impaired integrin binding activity effectively inhibit integrin activation. Consistent with previous reports, we find that when co-expressed with the talin head, kindlin-1 or -2 can activate alphaIIbbeta3. This effect is dependent on an intact integrin-binding site in kindlin. Notably however, even when co-expressed with activating levels of talin head, neither kindlin-1 or -2 can cooperate with talin to activate beta1 integrins; instead they strongly inhibit talin-mediated activation. We suggest that kindlins are adaptor proteins that regulate integrin activation, that kindlin expression levels determine their effects, and that kindlins may exert integrin-specific effects.

Dataset Information

An interaction between {alpha}v{beta}8 integrin and Band 4.1B via a highly conserved region of the Band 4.1 C-terminal domain.

Publications

An interaction between {alpha}v{beta}8 integrin and Band 4.1B via a highly conserved region of the Band 4.1 C-terminal domain.

Similar Datasets

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