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Review
. 2017 Feb 18;10(1):50.
doi: 10.1186/s13045-017-0418-y.

Paxillin: a crossroad in pathological cell migration

Ana María López-Colomé  1 , Irene Lee-Rivera  2 , Regina Benavides-Hidalgo  2 , Edith López  2
Affiliations
Review

Paxillin: a crossroad in pathological cell migration

Ana María López-Colomé et al. J Hematol Oncol. .

Abstract

Paxilllin is a multifunctional and multidomain focal adhesion adapter protein which serves an important scaffolding role at focal adhesions by recruiting structural and signaling molecules involved in cell movement and migration, when phosphorylated on specific Tyr and Ser residues. Upon integrin engagement with extracellular matrix, paxillin is phosphorylated at Tyr31, Tyr118, Ser188, and Ser190, activating numerous signaling cascades which promote cell migration, indicating that the regulation of adhesion dynamics is under the control of a complex display of signaling mechanisms. Among them, paxillin disassembly from focal adhesions induced by extracellular regulated kinase (ERK)-mediated phosphorylation of serines 106, 231, and 290 as well as the binding of the phosphatase PEST to paxillin have been shown to play a key role in cell migration. Paxillin also coordinates the spatiotemporal activation of signaling molecules, including Cdc42, Rac1, and RhoA GTPases, by recruiting GEFs, GAPs, and GITs to focal adhesions. As a major participant in the regulation of cell movement, paxillin plays distinct roles in specific tissues and developmental stages and is involved in immune response, epithelial morphogenesis, and embryonic development. Importantly, paxillin is also an essential player in pathological conditions including oxidative stress, inflammation, endothelial cell barrier dysfunction, and cancer development and metastasis.

Keywords: Cancer; Cell migration; Focal adhesions; Signal transduction.

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Figures

Fig. 1
Fig. 1
Paxillin at focal adhesions. As a major component of FAs, the phosphorylation of paxillin by FAK upon integrin activation allows the recruitment of several enzymes and structural molecules. Dynamics of paxillin association with these molecules results in changes in cell movement and migration. The figure depicts a simplified scheme showing the main components of a focal adhesion complex. The number and composition of the FA complex and the related signaling pathways may vary in different scenarios, according to the subunit composition of integrin receptors and the specific signaling pathways activated by distinct combinations, in addition to the type and developmental stage of the cell [44]
Fig. 2
Fig. 2
Human paxillin gene map. a Exon–intron organization. The gene spans over 55 kb of genomic region in chromosome 12q24 and contains at least 20 exons (shown in boxes). Exons contained in isoforms 1–4 are shown in color, whereas exons contained in predicted alternative splice variants are shown as white boxes. The alternative initiation sites, as well as the alternative 5’ donor sites or 3’ acceptor sites are depicted with dashed lines. The assembly of isoforms 1–4 is shown below. The position of the exons, as well as their inclusion in the different isoforms, is shown in Additional file 1. The nucleotide sequence of the human paxillin genomic sequences (Gene ID: 5829) containing exons and introns corresponds to GenBank with accession number NC_000012; REGION: complement (120210439..120265771) GPC_000001304. b Promoter region. Ensembl Regulatory Element ENSR00000091396 contains PXN promoter. This region spans 3401 bp region: 1271 bp upstream and 2130 bp downstream the transcription start site (TSS). Only experimentally validated regulatory elements are shown [–16]
Fig. 3
Fig. 3
Paxillin structural and functional organization. Human paxillin protein includes 591 amino acids. The N-terminus contains a proline-rich region that anchors SH3-containing proteins and five leucine-rich LD domains (LD1–LD5), which include docking sequences for the recruitment of signaling and structural molecules such as FAK, vinculin, and Crk. The C-terminus contains four cystein-histidine-enriched LIM domains, involved in the anchoring of paxillin to the plasma membrane and its targeting to focal adhesions. Paxillin is phosphorylated in response to cell adhesion and cytokine or growth factor stimulation: Tyrosine phosphorylation generates interaction sites for signaling molecules, which in turn regulate paxillin targeting to FAs. Serine phosphorylation, results in a number of functional modifications involved in the regulation of the adhesion process and cell movement
Fig. 4
Fig. 4
Activation of signaling pathways linked to paxillin phosphorylation. The localization of paxillin and the subsequent recruitment of signaling and adapter proteins are highly dependent on phosphorylation. Tyrosine phosphorylation of paxillin promotes the binding of SH2 domain-containing signaling proteins. In turn, paxillin is also a target for multiple upstream signaling pathways, which upon phosphorylation of specific serine residues modulate the expression, turnover, and intracellular localization of paxillin
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