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Integrin LFA-1 interacts with the transcriptional co-activator JAB1 to modulate AP-1 activity

Abstract

Integrin adhesion receptors transduce signals that control complex cell functions which require the regulation of gene expression, such as proliferation, differentiation and survival1. Their intracellular domain has no catalytic function, indicating that interaction with other transducing molecules is crucial for integrin-mediated signalling. Here we have identified a protein that interacts with the cytoplasmic domain of the β2 subunit of the αL/β2 integrin LFA-1. This protein is JAB1 (Jun activation domain-binding protein 1), a coactivator of the c-Jun transcription factor2. We found that JAB1 is present both in the nucleus and in the cytoplasm of cells and that a fraction of JAB1 colocalizes with LFA-1 at the cell membrane. LFA-1 engagement is followed by an increase of the nuclear pool of JAB1, paralleled by enhanced binding of c-Jun-containing AP-1 complexes to their DNA consensus site and increased transactivation of an AP-1-dependent promoter. We suggest that signalling through the LFA-1 integrin may affect c-Jun-driven transcription by regulating JAB1 nuclear localization. This represents a new pathway for integrin-dependent modulation of gene expression.

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Figure 1: JAB1 binds to the cytoplasmic domain of the LFA-1 β2 chain.
Figure 2: JAB1 colocalizes with LFA-1 in COS7 cells and is enriched in the nucleus upon LFA-1 aggregation.
Figure 3: JAB1 is enriched in the nuclear fraction after LFA-1 stimulation.
Figure 4: LFA-1 stimulation synergizes with JAB1 in inducing AP-1 transcriptional activity.

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Acknowledgements

We thank S. Putignano for generating anti-JAB1 MoAb, S. Biffo for GST-TrkB, M. Karin for the GST-c-Jun and the c-JunA63/73 constructs, A. Cassetti for help with confocal microscopy, S. Trinca for administrative assistance and V. Zimarino for critically reviewing the manuscript. This work was supported by grants from AIRC, Telethon and MURST (to R.P.).

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Correspondence to Elisabetta Bianchi.

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Bianchi, E., Denti, S., Granata, A. et al. Integrin LFA-1 interacts with the transcriptional co-activator JAB1 to modulate AP-1 activity. Nature 404, 617–621 (2000). https://doi.org/10.1038/35007098

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