Paxillin is aprotein that in humans is encoded by thePXNgene. Paxillin is expressed atfocal adhesions of non-striated cells and atcostameres ofstriated muscle cells, and it functions to adhere cells to theextracellular matrix. Mutations inPXN as well as abnormal expression of paxillin protein has been implicated in the progression of various cancers.
Paxillin is asignal transductionadaptor protein discovered in 1990 in the laboratory ofKeith Burridge[13] The C-terminal region of paxillin contains fourLIM domains that target paxillin tofocal 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 proteintyrosine kinases, such asSrc andfocal adhesion kinase (FAK), structural proteins, such asvinculin 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 proteinCrk.
Instriated muscle cells, paxillin is important in costamerogenesis, or the formation ofcostameres, which are specializedfocal adhesion-like structures in muscle cells that tetherZ-disc structures across thesarcolemma to theextracellular matrix. The current working model of costamerogenesis is that in cultured, undifferentiatedmyoblasts,alpha-5 integrin,vinculin and paxillin are in complex and located primarily atfocal adhesions. During early differentiation, premyofibril formation throughsarcomerogenesis occurs, and premyofibrils assemble at structures that are typical offocal adhesions in non-muscle cells; a similar phenomenon is observed in culturedcardiomyocytes.[15] Premyofibrils become nascent myofibrils, which progressively align to form maturemyofibrils and nascentcostamere structures appear. Costameric proteins redistribute to form maturecostameres.[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. Theproline-rich region of paxillin specifically binds to the secondSH3 domain ofponsin, which occurs after the onset of the myogenic differentiation and with expression restricted tocostameres.[17] We also know that the binding of paxillin tofocal adhesion kinase (FAK) is critical for directing paxillin function. Thephosphorylation ofFAK atserine-910 regulates the interaction ofFAK with paxillin, and controls the stability of paxillin atcostameres incardiomyocytes, withphosphorylation reducing thehalf-life of paxillin.[18] This is important to understand because the stability of theFAK-paxillin interaction is likely inversely related to the stability of thevinculin-paxillin interaction, which would likely indicate the strength of thecostamere interaction as well assarcomere reorganization; processes which have been linked todilated cardiomyopathy.[19] Additional studies have shown that paxillin itself is phosphorylated, and this participates inhypertrophic signaling pathways incardiomyocytes. Treatment ofcardiomyocytes with the hypertrophic agonist,phenylephrine stimulated a rapid increase intyrosinephosphorylation paxillin, which was mediated by proteintyrosine kinases.[20]
The structural reorganization of paxillin incardiomyocytes has also been detected in mouse models ofdilated cardiomyopathy. In a mouse model oftropomodulin overexpression, paxillin distribution was revamped coordinate with increasedphosphorylation and cleavage of paxillin.[21] Similarly, paxillin was shown to have altered localization incardiomyocytes from transgenic mice expressing a constitutively-activerac1.[22] These data show that alterations incostameric organization, in part via paxillin redistribution, may be a pathogenic mechanism indilated cardiomyopathy. In addition, in mice subjected to pressure overload-inducedcardiac hypertrophy, inducinghypertrophic cardiomyopathy, paxillin expression levels increased, suggesting a role for paxillin in both types ofcardiomyopathy.[23]
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 ofhyperplasia,squamous metaplasia andgoblet cell metaplasia, as well as dysplastic lesions andcarcinoma in high-risk patients withlung adenocarcinoma.[24] Mutations inPXN 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 andphosphorylated.[26] Paxillin plays a role in the MET tyrosine kinase signaling pathway, which is upregulated in many cancers.[27]
^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.PMID9699628.S2CID9635426.
^abGehmlich 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.PMID17462669.
^Wood CK, Turner CE, Jackson P, Critchley DR (February 1994). "Characterisation of the paxillin-binding site and the C-terminal focal adhesion targeting sequence in vinculin".Journal of Cell Science.107 (2):709–17.doi:10.1242/jcs.107.2.709.PMID8207093.
^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.doi:10.1242/jcs.107.6.1583.PMID7525621.
Salgia R, Sattler M, Pisick E, Li JL, Griffin JD (February 1996). "p210BCR/ABL induces formation of complexes containing focal adhesion proteins and the protooncogene product p120c-Cbl".Experimental Hematology.24 (2):310–3.PMID8641358.
