Paxillin is a
protein that in humans is encoded by the PXNgene. 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.[5]
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-terminalYXX
P motifs may serve as binding sites for
talin or
v-Crk SH2.[11][12]
Function
Paxillin is a
signal transductionadaptor 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
tyrosinephosphorylation 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]
^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.
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^
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.