HGNC Approved Gene Symbol: PXN
Cytogenetic location: 12q24.23 Genomic coordinates (GRCh38) : 12:120,210,447-120,265,730 (from NCBI)
Glenney and Zokas (1989) used an antiphosphotyrosine antibody to identify proteins that are phosphorylated in Rous sarcoma virus-transformed chick embryo fibroblasts, and found a 76-kD protein that localizes to focal adhesions at the ends of actin-containing stress fibers in nontransformed cells. Turner et al. (1990) purified this protein from chicken gizzard smooth muscle, and named it paxillin ('paxillus' means 'small stake' or 'peg' in Latin) as a protein tethered to the membrane at focal adhesions. Paxillin migrates as a diffuse 65- to 70-kD band on SDS-PAGE. Salgia et al. (1995) stated that transmembrane integrin molecules (see 600536) connect the actin cytoskeleton to the extracellular matrix within focal adhesions. They cloned human paxillin by screening an expression library with antipaxillin antibody. The predicted 557-amino acid protein has a predicted molecular mass of 61 kD, but an observed molecular mass of 68 kD, suggesting that it is either posttranslationally modified or migrates aberrantly due to high (10%) proline content. The paxillin protein contains 4 LIM domains, a proline-rich domain containing a consensus SH3-binding site, and 3 potential SH2-binding sites. On Northern blots, paxillin was expressed as a 3.7-kb mRNA in all tissues tested.
Mazaki et al. (1997) found that the paxillin gene can be alternatively spliced to include 1 of 2 alternative exons, generating beta and gamma isoforms. As observed on Northern blots, Western blots, and with RT-PCR, the beta and gamma isoforms are expressed only in certain cancer cell lines. The different isoforms had different affinities for cellular proteins, including vinculin (193065) and FAK (600758), suggesting that each acts as a distinct module involved in different functions of integrins.
Neurofibromatosis type II (101000) is an autosomal dominant disorder characterized by tumors, predominantly schwannomas, in the nervous system. It is caused by mutations in the NF2 gene (607379), which encodes the growth regulator schwannomin (also known as merlin). Mutations occur throughout the 17-exon gene, with most resulting in protein truncation and undetectable amounts of schwannomin protein. Pathogenic mutations that result in production of defective schwannomin include in-frame deletions of exon 2 and 3 independent missense mutations within this same exon, e.g., phe62 to ser (607379.0016). Mice with conditional deletion of exon 2 in Schwann cells develop schwannomas, which confirms the crucial nature of exon 2 for growth control. Fernandez-Valle et al. (2002) reported that paxillin binds directly to schwannomin at residues 50-70, which are encoded by exon 2. This interaction mediates the membrane localization of schwannomin to the plasma membrane, where it associates with beta-1-integrin (ITGB1; 135630) and ERBB2 (164870).
Using immunoprecipitation and pull-down experiments in chick embryonic fibroblasts (CEFs), Denhez et al. (2002) showed that syndesmos (NUDT16L1; 617338) interacted with paxillin. Activation of protein kinase C (see 176960) in serum-starved CEFs triggered interaction of paxillin with syndesmos. Interaction of paxillin with syndesmos could be stabilized briefly by orthovanadate treatment, indicating a dependence on tyrosine phosphorylation.
Huang et al. (2003) found that JNK1 (601158) phosphorylates paxillin, a focal adhesion adaptor, on serine-178 both in vitro and in intact cells. Rat bladder tumor epithelial cells expressing the ser178-to-ala mutant of paxillin formed focal adhesions and exhibited the limited movement associated with such contacts in both single-cell-migration and wound-healing assays. In contrast, cells expressing wildtype paxillin moved rapidly and retained close contacts as the predominant adhesion. Expression of mutant paxillin also inhibited the migration of 2 other cell lines. Thus, Huang et al. (2003) concluded that phosphorylation of paxillin by JNK seems essential for maintaining the labile adhesions required for rapid cell migration.
Activation of hepatocyte growth factor (HGF; 142409) receptor (MET; 164860) in epithelial cells results in lamellipodia protrusion, spreading, migration, and tubule formation. Ishibe et al. (2004) found that activated Erk (see MAPK3; 601795) phosphorylated mouse paxillin on ser83 and that mutation at this site eliminated HGF-stimulated association of paxillin and Fak in subconfluent mouse inner medullary collecting duct cells. Expression of paxillin mutants that disrupted Erk association or phosphorylation inhibited HGF-induced cell spreading, migration, and tubulogenesis.
Kanchanawong et al. (2010) used 3-dimensional super-resolution fluorescence microscopy to map nanoscale protein organization in focal adhesions. Their results revealed that integrins and actin are vertically separated by an approximately 40-nm focal adhesion core region consisting of multiple protein-specific strata: a membrane-apposed integrin signaling layer containing integrin cytoplasmic tails (see 193210), focal adhesion kinase (600758), and paxillin; an intermediate force-transduction layer containing talin (186745) and vinculin (193065); and an uppermost actin-regulatory layer containing zyxin (602002), vasodilator-stimulated phosphoprotein (601703), and alpha-actinin (102575). By localizing amino- and carboxy-terminally tagged talins, Kanchanawong et al. (2010) revealed talin's polarized orientation, indicative of a role in organizing the focal adhesion strata. Kanchanawong et al. (2010) concluded that their composite multilaminar protein architecture provided a molecular blueprint for understanding focal adhesion functions.
Salgia et al. (1995) mapped the paxillin gene to 12q24 using fluorescence in situ hybridization.
Denhez, F., Wilcox-Adelman, S. A., Baciu, P. C., Saoncella, S., Lee, S., French, B., Neveu, W., Goetinck, P. F. Syndesmos, a syndecan-4 cytoplasmic domain interactor, binds to the focal adhesion adaptor proteins paxillin and hic-5. J. Biol. Chem. 277: 12270-12274, 2002. [PubMed: 11805099] [Full Text: https://doi.org/10.1074/jbc.M110291200]
Fernandez-Valle, C., Tang, Y., Ricard, J., Rodenas-Ruano, A., Taylor, A., Hackler, E., Biggerstaff, J., Iacovelli, J. Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology. Nature Genet. 31: 354-362, 2002. [PubMed: 12118253] [Full Text: https://doi.org/10.1038/ng930]
Glenney, J. R., Jr., Zokas, L. Novel tyrosine kinase substrates from Rous sarcoma virus-transformed cells are present in the membrane skeleton. J. Cell Biol. 108: 2401-2408, 1989. [PubMed: 2472406] [Full Text: https://doi.org/10.1083/jcb.108.6.2401]
Huang, C., Rajfur, Z., Borchers, C., Schaller, M. D., Jacobson, K. JNK phosphorylates paxillin and regulates cell migration. Nature 424: 219-223, 2003. [PubMed: 12853963] [Full Text: https://doi.org/10.1038/nature01745]
Ishibe, S., Joly, D., Liu, Z.-X., Cantley, L. G. Paxillin serves as an ERK-regulated scaffold for coordinating FAK and Rac activation in epithelial morphogenesis. Molec. Cell 16: 257-267, 2004. [PubMed: 15494312] [Full Text: https://doi.org/10.1016/j.molcel.2004.10.006]
Kanchanawong, P., Shtengel, G., Pasapera, A. M., Ramko, E. B., Davidson, M. W., Hess, H. F., Waterman, C. M. Nanoscale architecture of integrin-based cell adhesions. Nature 468: 580-584, 2010. [PubMed: 21107430] [Full Text: https://doi.org/10.1038/nature09621]
Mazaki, Y., Hashimoto, S., Sabe, H. Monocyte cells and cancer cells express novel paxillin isoforms with different binding properties to focal adhesion proteins. J. Biol. Chem. 272: 7437-7444, 1997. [PubMed: 9054445] [Full Text: https://doi.org/10.1074/jbc.272.11.7437]
Salgia, R., Li, J.-L., Lo, S. H., Brunkhorst, B., Kansas, G. S., Sobhany, E. S., Sun, Y., Pisick, E., Hallek, M., Ernst, T., Tantravahi, R., Chen, L. B., Griffin, J. D. Molecular cloning of human paxillin, a focal adhesion protein phosphorylated by P210(BCR/ABL). J. Biol. Chem. 270: 5039-5047, 1995. [PubMed: 7534286] [Full Text: https://doi.org/10.1074/jbc.270.10.5039]
Turner, C. E., Glenney, J. R., Jr., Burridge, K. Paxillin: a new vinculin-binding protein present in focal adhesions. J. Cell Biol. 111: 1059-1068, 1990. [PubMed: 2118142] [Full Text: https://doi.org/10.1083/jcb.111.3.1059]