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Review
. 2022 Apr 5:10:852016.
doi: 10.3389/fcell.2022.852016. eCollection 2022.

Paxillin: A Hub for Mechano-Transduction from the β3 Integrin-Talin-Kindlin Axis

Marta Ripamonti  1 , Bernhard Wehrle-Haller  2 , Ivan de Curtis  1
Affiliations
Review

Paxillin: A Hub for Mechano-Transduction from the β3 Integrin-Talin-Kindlin Axis

Marta Ripamonti et al. Front Cell Dev Biol. .

Abstract

Focal adhesions are specialized integrin-dependent adhesion complexes, which ensure cell anchoring to the extracellular matrix. Focal adhesions also function as mechano-signaling platforms by perceiving and integrating diverse physical and (bio)chemical cues of their microenvironment, and by transducing them into intracellular signaling for the control of cell behavior. The fundamental biological mechanism of creating intracellular signaling in response to changes in tensional forces appears to be tightly linked to paxillin recruitment and binding to focal adhesions. Interestingly, the tension-dependent nature of the paxillin binding to adhesions, combined with its scaffolding function, suggests a major role of this protein in integrating multiple signals from the microenvironment, and accordingly activating diverse molecular responses. This minireview offers an overview of the molecular bases of the mechano-sensitivity and mechano-signaling capacity of core focal adhesion proteins, and highlights the role of paxillin as a key component of the mechano-transducing machinery based on the interaction of cells to substrates activating the β3 integrin-talin1-kindlin.

Keywords: integrin activation; lim domain; mechano-sensing; plasma membrane; tensional force.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic representation of core FA proteins and their interactions. The β3 integrin subunit is composed of an extracellular domain, a transmembrane domain, and a C-terminal cytoplasmic tail presenting the membrane proximal NPLY talin-binding and membrane distal NITY kindlin-binding sites. The heterodimeric integrin receptor in a bent-close low-affinity conformation (left) switches to an extended-open high-affinity state and binds ligands and intracellular proteins (right). Talin1 consists of a globular head, an unstructured linker, and a C-terminal rod domain which intramolecularly interacts with the head domain to keep cytosolic talin1 auto-inhibited. Upon integrin activation, the talin1 F2 domain binds to membrane phospholipid PI(4,5)P2, the talin F3 subdomain to the membrane proximal NPLY motif in the β3 integrin cytoplasmic tail, and the talin rod engages the F-actin network. Kindlin is similarly organized to talin-head but with the addition of a PH domain inserted within the F2 domain which recognizes membrane phosphoinositides, while the F3 domain binds to the membrane-distal NITY motif in the β3 integrin cytoplasmic tail. The paxillin amino-terminal half presents five short LD motifs and is followed by the carboxyl-terminal half composed of four LIM domains. The paxillin N-terminal LD1 and LD2 interact with the talin1 R8 domain, the LIM domains point towards the membrane proximal region, the positively charged LIM4 domain interacts with kindlin and the plasma membrane. One of the paxillin LIM domain could recognize the Y presented by the NPLY motif. +++ indicates positively charged regions. For representative purposes, the β3 integrin tail is outsized and some protein domains are simplified or omitted for clarity.
FIGURE 2
FIGURE 2
Temporal sequence of β3 integrin activation and paxillin-mediated organization of adhesions. (A), Schematic representation of FA assembly over time. Ligand, talin and kindlin binding to integrin receptors triggers their clustering, mediates the mechanical connection with the F-actin network, and recruits cytoplasmic proteins. (B), Paxillin is a structural, signaling and linker component of FAs. C-terminal LIM domains target paxillin to FAs, possibly directly interacting with talin, kindlin, and β3 integrin (putative domains indicated). The paxillin N-terminus functions as a signaling molecule, binding/recruiting different subsets of FA proteins, modulating F-actin polymerization and tension within adhesions, and therefore generating feedback signaling which can lead to FA turnover.
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References

    1. Alam T., Alazmi M., Naser R., Huser F., Momin A. A., Astro V., et al. (2020). Proteome-level Assessment of Origin, Prevalence and Function of Leucine-Aspartic Acid (LD) Motifs. Bioinformatics 36, 1121–1128. 10.1093/bioinformatics/btz703 - DOI - PMC - PubMed
    1. Alam T., Alazmi M., Gao X., Arold S. T. (2014). How to Find a Leucine in a Haystack? Structure, Ligand Recognition and Regulation of Leucine-Aspartic Acid (LD) Motifs. Biochem. J. 460, 317–329. 10.1042/bj20140298 - DOI - PubMed
    1. Anthis N. J., Wegener K. L., Critchley D. R., Campbell I. D. (2010). Structural Diversity in Integrin/talin Interactions. Structure 18, 1654–1666. 10.1016/j.str.2010.09.018 - DOI - PMC - PubMed
    1. Anthis N. J., Wegener K. L., Ye F., Kim C., Goult B. T., Lowe E. D., et al. (2009). The Structure of an Integrin/talin Complex Reveals the Basis of Inside-Out Signal Transduction. EMBO J. 28, 3623–3632. 10.1038/emboj.2009.287 - DOI - PMC - PubMed
    1. Atherton P., Lausecker F., Carisey A., Gilmore A., Critchley D., Barsukov I., et al. (2020). Relief of Talin Autoinhibition Triggers a Force-independent Association with Vinculin. J. Cel Biol 219, e201903134. 10.1083/jcb.201903134 - DOI - PMC - PubMed

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