Paxillin

Paxillin is a protein that in humans is encoded by the PXN gene. Paxillin is expressed at focal adhesions of non-striated cells and at costameres of striated muscle cells, and it functions to adhere cells to the extracellular matrix. Mutations in PXN as well as abnormal expression of paxillin protein has been implicated in the progression of various cancers.

Not to be confused with the neurotoxin paxilline.

PXN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPXN, entrez:5829, paxillin
External IDsOMIM: 602505 MGI: 108295 HomoloGene: 37697 GeneCards: PXN
Gene location (Human)
Chr.Chromosome 12 (human)[1]
Band12q24.23Start120,210,439 bp[1]
End120,265,771 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

5829

19303

Ensembl

ENSG00000089159

ENSMUSG00000029528

UniProt

P49023

Q8VI36

RefSeq (mRNA)

NM_001080855
NM_001243756
NM_002859
NM_025157

NM_011223
NM_133915

RefSeq (protein)

NP_001074324
NP_001230685
NP_002850
NP_079433

NP_035353
NP_598676

Location (UCSC)Chr 12: 120.21 – 120.27 MbChr 5: 115.51 – 115.56 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

Human paxillin is 64.5 kDa in molecular weight and 591 amino acids in length.[5]

The C-terminal region of paxillin is composed of four tandem double zinc finger LIM domains that are cysteine/histidine-rich with conserved repeats; these serve as binding sites for the protein tyrosine phosphatase-PEST,[6] tubulin[7] and serves as the targeting motif for focal adhesions.[8]

The N-terminal region of paxillin has five highly conserved leucine-rich sequences termed LD motifs, which mediate several interactions, including that with pp125FAK and vinculin.[9][10] The LD motifs are predicted to form amphipathic alpha helices, with each leucine residue positioned on one face of the alpha helix to form a hydrophobic protein-binding interface. The N-terminal region also has a proline-rich domain that has potential for Src-SH3 binding. Three N-terminal YXXP motifs may serve as binding sites for talin or v-Crk SH2.[11][12]

Function

Paxillin is a signal transduction adaptor protein discovered in 1990 in the laboratory of Keith Burridge[13] The C-terminal region of paxillin contains four LIM domains that target paxillin to focal adhesions. It is presumed through a direct association with the cytoplasmic tail of beta-integrin. The N-terminal region of paxillin is rich in protein–protein interaction sites. The proteins that bind to paxillin are diverse and include protein tyrosine kinases, such as Src and focal adhesion kinase (FAK), structural proteins, such as vinculin and actopaxin, and regulators of actin organization, such as COOL/PIX and PKL/GIT. Paxillin is tyrosine-phosphorylated by FAK and Src upon integrin engagement or growth factor stimulation,[14] creating binding sites for the adapter protein Crk.

In striated muscle cells, paxillin is important in costamerogenesis, or the formation of costameres, which are specialized focal adhesion-like structures in muscle cells that tether Z-disc structures across the sarcolemma to the extracellular matrix. The current working model of costamerogenesis is that in cultured, undifferentiated myoblasts, alpha-5 integrin, vinculin and paxillin are in complex and located primarily at focal adhesions. During early differentiation, premyofibril formation through sarcomerogenesis occurs, and premyofibrils assemble at structures that are typical of focal adhesions in non-muscle cells; a similar phenomenon is observed in cultured cardiomyocytes.[15] Premyofibrils become nascent myofibrils, which progressively align to form mature myofibrils and nascent costamere structures appear. Costameric proteins redistribute to form mature costameres.[16] While the precise functions of paxillin in this process are still being unveiled, studies investigating binding partners of paxillin have provided mechanistic understanding of its function. The proline-rich region of paxillin specifically binds to the second SH3 domain of ponsin, which occurs after the onset of the myogenic differentiation and with expression restricted to costameres.[17] We also know that the binding of paxillin to focal adhesion kinase (FAK) is critical for directing paxillin function. The phosphorylation of FAK at serine-910 regulates the interaction of FAK with paxillin, and controls the stability of paxillin at costameres in cardiomyocytes, with phosphorylation reducing the half-life of paxillin.[18] This is important to understand because the stability of the FAK-paxillin interaction is likely inversely related to the stability of the vinculin-paxillin interaction, which would likely indicate the strength of the costamere interaction as well as sarcomere reorganization; processes which have been linked to dilated cardiomyopathy.[19] Additional studies have shown that paxillin itself is phosphorylated, and this participates in hypertrophic signaling pathways in cardiomyocytes. Treatment of cardiomyocytes with the hypertrophic agonist, phenylephrine stimulated a rapid increase in tyrosine phosphorylation paxillin, which was mediated by protein tyrosine kinases.[20]

The structural reorganization of paxillin in cardiomyocytes has also been detected in mouse models of dilated cardiomyopathy. In a mouse model of tropomodulin overexpression, paxillin distribution was revamped coordinate with increased phosphorylation and cleavage of paxillin.[21] Similarly, paxillin was shown to have altered localization in cardiomyocytes from transgenic mice expressing a constitutively-active rac1.[22] These data show that alterations in costameric organization, in part via paxillin redistribution, may be a pathogenic mechanism in dilated cardiomyopathy. In addition, in mice subjected to pressure overload-induced cardiac hypertrophy, inducing hypertrophic cardiomyopathy, paxillin expression levels increased, suggesting a role for paxillin in both types of cardiomyopathy.[23]

Clinical significance

Paxillin has been shown to have a clinically-significant role in patients with several cancer types. Enhanced expression of paxillin has been detected in premalignant areas of hyperplasia, squamous metaplasia and goblet cell metaplasia, as well as dysplastic lesions and carcinoma in high-risk patients with lung adenocarcinoma.[24] Mutations in PXN have been associated with enhanced tumor growth, cell proliferation, and invasion in lung cancer tissues.[25]

During tumor transformation, a consistent finding is that paxillin protein is recruited and phosphorylated.[26] Paxillin plays a role in the MET tyrosine kinase signaling pathway, which is upregulated in many cancers.[27]

Interactions

Paxillin has been shown to interact with:

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References
  1. GRCh38: Ensembl release 89: ENSG00000089159 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000029528 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Protein sequence of human PXN (Uniprot ID: P49023)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on July 13, 2015. Retrieved July 13, 2015.
  6. Shen Y, Schneider G, Cloutier JF, Veillette A, Schaller MD (March 1998). "Direct association of protein-tyrosine phosphatase PTP-PEST with paxillin". The Journal of Biological Chemistry. 273 (11): 6474–81. doi:10.1074/jbc.273.11.6474. PMID 9497381.
  7. Herreros L, Rodríguez-Fernandez JL, Brown MC, Alonso-Lebrero JL, Cabañas C, Sánchez-Madrid F, Longo N, Turner CE, Sánchez-Mateos P (August 2000). "Paxillin localizes to the lymphocyte microtubule organizing center and associates with the microtubule cytoskeleton" (PDF). The Journal of Biological Chemistry. 275 (34): 26436–40. doi:10.1074/jbc.M003970200. PMID 10840040.
  8. Côté JF, Turner CE, Tremblay ML (July 1999). "Intact LIM 3 and LIM 4 domains of paxillin are required for the association to a novel polyproline region (Pro 2) of protein-tyrosine phosphatase-PEST". The Journal of Biological Chemistry. 274 (29): 20550–60. doi:10.1074/jbc.274.29.20550. PMID 10400685.
  9. Brown MC, Curtis MS, Turner CE (August 1998). "Paxillin LD motifs may define a new family of protein recognition domains". Nature Structural Biology. 5 (8): 677–8. doi:10.1038/1370. PMID 9699628.
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  17. Gehmlich K, Pinotsis N, Hayess K, van der Ven PF, Milting H, El Banayosy A, Körfer R, Wilmanns M, Ehler E, Fürst DO (June 2007). "Paxillin and ponsin interact in nascent costameres of muscle cells". Journal of Molecular Biology. 369 (3): 665–82. doi:10.1016/j.jmb.2007.03.050. PMID 17462669.
  18. Chu M, Iyengar R, Koshman YE, Kim T, Russell B, Martin JL, Heroux AL, Robia SL, Samarel AM (December 2011). "Serine-910 phosphorylation of focal adhesion kinase is critical for sarcomere reorganization in cardiomyocyte hypertrophy". Cardiovascular Research. 92 (3): 409–19. doi:10.1093/cvr/cvr247. PMC 3246880. PMID 21937583.
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  20. Taylor JM, Rovin JD, Parsons JT (June 2000). "A role for focal adhesion kinase in phenylephrine-induced hypertrophy of rat ventricular cardiomyocytes". The Journal of Biological Chemistry. 275 (25): 19250–7. doi:10.1074/jbc.M909099199. PMID 10749882.
  21. Melendez J, Welch S, Schaefer E, Moravec CS, Avraham S, Avraham H, Sussman MA (November 2002). "Activation of pyk2/related focal adhesion tyrosine kinase and focal adhesion kinase in cardiac remodeling". The Journal of Biological Chemistry. 277 (47): 45203–10. doi:10.1074/jbc.M204886200. PMID 12228222.
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  23. Yund EE, Hill JA, Keller RS (October 2009). "Hic-5 is required for fetal gene expression and cytoskeletal organization of neonatal cardiac myocytes". Journal of Molecular and Cellular Cardiology. 47 (4): 520–7. doi:10.1016/j.yjmcc.2009.06.006. PMC 3427732. PMID 19540241.
  24. Mackinnon AC, Tretiakova M, Henderson L, Mehta RG, Yan BC, Joseph L, Krausz T, Husain AN, Reid ME, Salgia R (January 2011). "Paxillin expression and amplification in early lung lesions of high-risk patients, lung adenocarcinoma and metastatic disease". Journal of Clinical Pathology. 64 (1): 16–24. doi:10.1136/jcp.2010.075853. PMC 3002839. PMID 21045234.
  25. Jagadeeswaran R, Surawska H, Krishnaswamy S, Janamanchi V, Mackinnon AC, Seiwert TY, Loganathan S, Kanteti R, Reichman T, Nallasura V, Schwartz S, Faoro L, Wang YC, Girard L, Tretiakova MS, Ahmed S, Zumba O, Soulii L, Bindokas VP, Szeto LL, Gordon GJ, Bueno R, Sugarbaker D, Lingen MW, Sattler M, Krausz T, Vigneswaran W, Natarajan V, Minna J, Vokes EE, Ferguson MK, Husain AN, Salgia R (January 2008). "Paxillin is a target for somatic mutations in lung cancer: implications for cell growth and invasion". Cancer Research. 68 (1): 132–42. doi:10.1158/0008-5472.CAN-07-1998. PMC 2767335. PMID 18172305.
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  29. Turner CE, Miller JT (June 1994). "Primary sequence of paxillin contains putative SH2 and SH3 domain binding motifs and multiple LIM domains: identification of a vinculin and pp125Fak-binding region". Journal of Cell Science. 107 (6): 1583–91. PMID 7525621.
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Further reading
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