Paxillin

Key takeaways

Paxillin belongs to biology; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect Paxillin to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Paxillin from memory before moving on to harder problems.

Reference excerpt

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. 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, tubulin and serves as the targeting motif for focal adhesions. 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. 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.

Function Paxillin is a signal transduction adaptor protein discovered in 1990 in the laboratory of Keith Burridge 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, 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. Premyofibrils become nascent myofibrils, which progressively align to form mature myofibrils and nascent costamere structures appear. Costameric proteins redistribute to form mature costameres. 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. We also know that the binding of paxillin to 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. 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. 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. 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. Similarly, paxillin was shown to have altered localization in cardiomyocytes from transgenic mice expressing a constitutively-active rac1. 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.

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. Mutations in PXN have been associated with enhanced tumor growth, cell proliferation, and invasion in lung cancer tissues. During tumor transformation, a consistent finding is that paxillin protein is recruited and phosphorylated. Paxillin plays a role in the MET tyrosine kinase signaling pathway, which is upregulated in many cancers.

Interactions Paxillin has been shown to interact with:

PTP-PEST, tubulin, VCL, pp125FAK. SRC SORBS1. PARVA and ILK

References

Illustrations

Worked examples

Example 1 — a first encounter with Paxillin

Start with the simplest possible case. Write down what Paxillin claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Paxillin before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Paxillin ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Paxillin

In research: Paxillin appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Paxillin in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Paxillin is common in secondary-school and first-year university syllabi. It links to neighbouring topics Genes on human chromosome 12, Proteins, so understanding it makes those chapters shorter.
In everyday life: Look for Paxillin outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study Paxillin in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Paxillin means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain Paxillin out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Paxillin in simple terms?

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.

Why does Paxillin matter?

Because it connects several biology ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Paxillin?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Paxillin.