Paxillin Explained

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.

Structure

Human paxillin is 64.5 kDa in molecular weight and 591 amino acids in length.[1]

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,[2] tubulin[3] and serves as the targeting motif for focal adhesions.[4]

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.[5] [6] 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.[7] [8]

Function

Paxillin is a signal transduction adaptor protein discovered in 1990 in the laboratory of Keith Burridge[9] 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,[10] 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.[11] Premyofibrils become nascent myofibrils, which progressively align to form mature myofibrils and nascent costamere structures appear. Costameric proteins redistribute to form mature costameres.[12] 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.[13] 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.[14] 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.[15] 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.[16]

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.[17] Similarly, paxillin was shown to have altered localization in cardiomyocytes from transgenic mice expressing a constitutively-active rac1.[18] 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.[19]

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.[20] Mutations in PXN have been associated with enhanced tumor growth, cell proliferation, and invasion in lung cancer tissues.[21]

During tumor transformation, a consistent finding is that paxillin protein is recruited and phosphorylated.[22] Paxillin plays a role in the MET tyrosine kinase signaling pathway, which is upregulated in many cancers.[23]

Interactions

Paxillin has been shown to interact with:

Further reading

External links

Notes and References

  1. Web site: Protein sequence of human PXN (Uniprot ID: P49023). Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 13 July 2015. https://web.archive.org/web/20150713223035/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P49023. July 13, 2015. dead.
  2. Shen Y, Schneider G, Cloutier JF, Veillette A, Schaller MD . Direct association of protein-tyrosine phosphatase PTP-PEST with paxillin . The Journal of Biological Chemistry . 273 . 11 . 6474–81 . Mar 1998 . 9497381 . 10.1074/jbc.273.11.6474. free .
  3. Herreros L, Rodríguez-Fernandez JL, Brown MC, Alonso-Lebrero JL, Cabañas C, Sánchez-Madrid F, Longo N, Turner CE, Sánchez-Mateos P . Paxillin localizes to the lymphocyte microtubule organizing center and associates with the microtubule cytoskeleton . The Journal of Biological Chemistry . 275 . 34 . 26436–40 . Aug 2000 . 10840040 . 10.1074/jbc.M003970200 . 10261/135387 . 9744939 . free .
  4. Côté JF, Turner CE, Tremblay ML . 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 . Jul 1999 . 10400685 . 10.1074/jbc.274.29.20550. free .
  5. Brown MC, Curtis MS, Turner CE . Paxillin LD motifs may define a new family of protein recognition domains . Nature Structural Biology . 5 . 8 . 677–8 . Aug 1998 . 9699628 . 10.1038/1370 . 9635426 .
  6. Tumbarello DA, Brown MC, Turner CE . The paxillin LD motifs . FEBS Letters . 513 . 1 . 114–8 . Feb 2002 . 11911889 . 10.1016/s0014-5793(01)03244-6. 26269466 . free .
  7. Salgia R, Li JL, Lo SH, Brunkhorst B, Kansas GS, Sobhany ES, Sun Y, Pisick E, Hallek M, Ernst T . Molecular cloning of human paxillin, a focal adhesion protein phosphorylated by P210BCR/ABL . The Journal of Biological Chemistry . 270 . 10 . 5039–47 . Mar 1995 . 7534286 . 10.1074/jbc.270.10.5039. free .
  8. Turner CE . Paxillin . The International Journal of Biochemistry & Cell Biology . 30 . 9 . 955–9 . Sep 1998 . 9785458 . 10.1016/s1357-2725(98)00062-4.
  9. Turner CE, Glenney JR, Burridge K . Paxillin: a new vinculin-binding protein present in focal adhesions . J. Cell Biol. . 111 . 3 . 1059–68 . 1990 . 2118142 . 2116264 . 10.1083/jcb.111.3.1059.
  10. Bellis SL, Miller JT, Turner CE . Characterization of tyrosine phosphorylation of paxillin in vitro by focal adhesion kinase . The Journal of Biological Chemistry . 270 . 29 . 17437–41 . Jul 1995 . 7615549 . 10.1074/jbc.270.29.17437. free .
  11. Decker ML, Simpson DG, Behnke M, Cook MG, Decker RS . Morphological analysis of contracting and quiescent adult rabbit cardiac myocytes in long-term culture . The Anatomical Record . 227 . 3 . 285–99 . Jul 1990 . 2372136 . 10.1002/ar.1092270303 . 41193996 .
  12. Quach NL, Rando TA . Focal adhesion kinase is essential for costamerogenesis in cultured skeletal muscle cells . Developmental Biology . 293 . 1 . 38–52 . May 2006 . 16533505 . 10.1016/j.ydbio.2005.12.040 . free .
  13. Gehmlich K, Pinotsis N, Hayess K, van der Ven PF, Milting H, El Banayosy A, Körfer R, Wilmanns M, Ehler E, Fürst DO . Paxillin and ponsin interact in nascent costameres of muscle cells . Journal of Molecular Biology . 369 . 3 . 665–82 . Jun 2007 . 17462669 . 10.1016/j.jmb.2007.03.050 .
  14. Chu M, Iyengar R, Koshman YE, Kim T, Russell B, Martin JL, Heroux AL, Robia SL, Samarel AM . Serine-910 phosphorylation of focal adhesion kinase is critical for sarcomere reorganization in cardiomyocyte hypertrophy . Cardiovascular Research . 92 . 3 . 409–19 . Dec 2011 . 21937583 . 10.1093/cvr/cvr247 . 3246880.
  15. Zemljic-Harpf AE, Miller JC, Henderson SA, Wright AT, Manso AM, Elsherif L, Dalton ND, Thor AK, Perkins GA, McCulloch AD, Ross RS . Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy . Molecular and Cellular Biology . 27 . 21 . 7522–37 . Nov 2007 . 17785437 . 10.1128/MCB.00728-07 . 2169049.
  16. Taylor JM, Rovin JD, Parsons JT . A role for focal adhesion kinase in phenylephrine-induced hypertrophy of rat ventricular cardiomyocytes . The Journal of Biological Chemistry . 275 . 25 . 19250–7 . Jun 2000 . 10749882 . 10.1074/jbc.M909099199 . free .
  17. Melendez J, Welch S, Schaefer E, Moravec CS, Avraham S, Avraham H, Sussman MA . Activation of pyk2/related focal adhesion tyrosine kinase and focal adhesion kinase in cardiac remodeling . The Journal of Biological Chemistry . 277 . 47 . 45203–10 . Nov 2002 . 12228222 . 10.1074/jbc.M204886200 . free .
  18. Sussman MA, Welch S, Walker A, Klevitsky R, Hewett TE, Price RL, Schaefer E, Yager K . Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active rac1 . The Journal of Clinical Investigation . 105 . 7 . 875–86 . Apr 2000 . 10749567 . 10.1172/JCI8497 . 377478.
  19. Yund EE, Hill JA, Keller RS . 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 . Oct 2009 . 19540241 . 10.1016/j.yjmcc.2009.06.006 . 3427732.
  20. Mackinnon AC, Tretiakova M, Henderson L, Mehta RG, Yan BC, Joseph L, Krausz T, Husain AN, Reid ME, Salgia R . 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 . Jan 2011 . 21045234 . 10.1136/jcp.2010.075853 . 3002839.
  21. 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 . Paxillin is a target for somatic mutations in lung cancer: implications for cell growth and invasion . Cancer Research . 68 . 1 . 132–42 . Jan 2008 . 18172305 . 10.1158/0008-5472.CAN-07-1998 . 2767335.
  22. Vande Pol SB, Brown MC, Turner CE . Association of Bovine Papillomavirus Type 1 E6 oncoprotein with the focal adhesion protein paxillin through a conserved protein interaction motif . Oncogene . 16 . 1 . 43–52 . Jan 1998 . 9467941 . 10.1038/sj.onc.1201504 . free .
  23. Lawrence RE, Salgia R . MET molecular mechanisms and therapies in lung cancer . Cell Adhesion & Migration . 4 . 1 . 146–52 . 2010 . 20139696 . 10.4161/cam.4.1.10973 . 2852571.
  24. Wood CK, Turner CE, Jackson P, Critchley DR . Characterisation of the paxillin-binding site and the C-terminal focal adhesion targeting sequence in vinculin . Journal of Cell Science . 107 . 709–17 . Feb 1994 . 8207093 . 2. 10.1242/jcs.107.2.709 .
  25. Turner CE, Miller JT . 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 . 1583–91 . Jun 1994 . 7525621 . 6. 10.1242/jcs.107.6.1583 .
  26. Hildebrand JD, Schaller MD, Parsons JT . Paxillin, a tyrosine phosphorylated focal adhesion-associated protein binds to the carboxyl terminal domain of focal adhesion kinase . Molecular Biology of the Cell . 6 . 6 . 637–47 . Jun 1995 . 7579684 . 10.1091/mbc.6.6.637 . 301225.
  27. Brown MC, Perrotta JA, Turner CE . Identification of LIM3 as the principal determinant of paxillin focal adhesion localization and characterization of a novel motif on paxillin directing vinculin and focal adhesion kinase binding . The Journal of Cell Biology . 135 . 4 . 1109–23 . Nov 1996 . 8922390 . 10.1083/jcb.135.4.1109 . 2133378.
  28. Turner CE . Paxillin interactions . Journal of Cell Science . 113 . 4139–40 . Dec 2000 . 11069756 . 23. 10.1242/jcs.113.23.4139 .
  29. Turner CE . Paxillin and focal adhesion signalling . Nature Cell Biology . 2 . 12 . E231-6 . Dec 2000 . 11146675 . 10.1038/35046659 . 26455236 .
  30. Nikolopoulos SN, Turner CE . Actopaxin, a new focal adhesion protein that binds paxillin LD motifs and actin and regulates cell adhesion . The Journal of Cell Biology . 151 . 7 . 1435–48 . Dec 2000 . 11134073 . 10.1083/jcb.151.7.1435 . 2150668.
  31. Nikolopoulos SN, Turner CE . Integrin-linked kinase (ILK) binding to paxillin LD1 motif regulates ILK localization to focal adhesions . The Journal of Biological Chemistry . 276 . 26 . 23499–505 . Jun 2001 . 11304546 . 10.1074/jbc.M102163200 . free .

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