Paxillin actions in the nucleus

Ma, Xiaoting; Hammes, Stephen R.

doi:10.1016/j.steroids.2017.10.012

Cited by 29 publications

(21 citation statements)

References 59 publications

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“…It contains four cysteine-histidine-enriched LIM domains that form zinc fingers, suggesting that PXN could bind DNA and act as a transcription factor. Consistently, PXN is reported to locate to the nucleus which is regulated by phosphorylation (Dong et al, 2009;Ma and Hammes, 2018). In LUAD, expression of PXN is correlated with tumor progression and metastasis (Song et al, 2010;Mackinnon et al, 2011).…”

Section: Introductionmentioning

confidence: 91%

A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis

Mohanty¹,

Nam²,

Pozhitkov³

et al. 2019

Preprint

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Tumor heterogeneity and cisplatin resistance are a major cause of tumor relapse and poor survival. Here we show that in lung adenocarcinoma (LUAD), paxillin (PXN) and integrin beta 4 (ITGB4) are associated with tumor progression, and cisplatin resistance. Silencing PXN and ITGB4 render cisplatin tolerant cells sensitive, and immunologically neutralizing ITGB4 improves sensitivity. The N-terminal half of PXN is intrinsically disordered and interacts with ITGB4 to regulate expression of USP1 and VDAC1 which are required for maintaining genomic stability and mitochondrial function in LUAD. By virtual screening an FDA-approved compound library, we identified compounds that interact with PXN in silico and attenuate cisplatin resistance in LUAD cells. RNAseq analysis identified a double negative feedback loop between ITGB4 and microRNA miR-1-3p, suggesting that bistability could lead to stochastic switching between cisplatinsensitive and resistant states in these cells. The data highlight an alternate, nongenetic, mechanism underlying chemoresistance in lung cancer.

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Section: Introductionmentioning

confidence: 91%

A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis

Mohanty¹,

Nam²,

Pozhitkov³

et al. 2019

Preprint

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“…For NSCs cultured on PDA-CF for 3 days, immunohistochemistry showed increased expression of vinculin protein ( Figure 7A ), and quantification of vinculin ( Figure 7B ) showed increased expression compared to the CF group, which suggests that PDA might promote NSC proliferation by regulating the expression of vinculin. The interaction between integrins and the ECM induces the expression of paxillin, which is a central component of focal adhesion complexes and plays a vital role in cell attachment, spreading, and migration through the transduction of extracellular signals into intracellular responses (Lo'pez-Colome et al, 2017 ; Ma and Hammes, 2018 ). Cells attach to the ECM through trans-membrane integrin proteins and use these interactions to sense their environment (Kechagia et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

A Polydopamine-Functionalized Carbon Microfibrous Scaffold Accelerates the Development of Neural Stem Cells

Yang

Zhang

Chai

et al. 2020

Front. Bioeng. Biotechnol.

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Neuroregenerative medicine has witnessed impressive technological breakthroughs in recent years, but the currently available scaffold materials still have limitations regarding the development of effective treatment strategies for neurological diseases. Electrically conductive micropatterned materials have gained popularity in recent years due to their significant effects on neural stem cell fate. Polydopamine (PDA)—modified materials can also enhance the differentiation of neurons. In this work, we show that PDA-modified carbon microfiber skeleton composites have the appropriate conductivity, three-dimensional structure, and microenvironment regulation that are crucial for the growth of neural stem cells. The design we present is low-cost and easy to make and shows great promise for studying the growth and development of mouse neural stem cells. Our results show that the PDA-mediated formation of electrically conductive and viscous nanofiber webs promoted the adhesion, organization, and intercellular coupling of neural stem cells relative to the control group. PDA induced massive proliferation of neural stem cells and promoted the expression of Ki-67. Together, our results suggest that the composite material can be used as a multifunctional neural scaffold for clinical treatment and in vitro research by improving the structure, conductivity, and mechanical integrity of the regenerated tissues.

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“…Hence this will affect proper JNK activation and AP-1 transcription factor activation thereby providing a positive feedback for EGFR expression [62] . Alternatively, paxillin may affect the expression of EGFR by its known role in the regulation of gene expression through its interaction with ERK [63,64] , poly-A-binding protein [65] , Abl [66,67] and steroid receptors, or through its own ability to undergo nucleocytoplasmic shuttling [37,38,[68][69][70][71] .…”

Section: Discussionmentioning

confidence: 99%

“…Paxillin is a 68 kD multidomain adaptor protein associated with focal adhesions [26][27][28][29][30][31] . It is long known to function as a scaffold to integrate multiple signaling pathways involved in matrix adhesion dynamics and cell migration [27,[31][32][33][34][35][36] , and recently, it was shown to play a role in the nucleus in relation to mRNA transcription and subsequent translation [37,38] . Few studies have identified paxillin as a JNK substrate [8,24,25] .…”

Section: Introductionmentioning

confidence: 99%

Paxillin serine 178 phosphorylation in control of cell migration and metastasis formation through regulation of EGFR expression in breast cancer

Verkoeijen¹,

Ma²,

Roosmalen³

et al. 2019

JCMT

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Aim: Paxillin is a well-known multidomain scaffold protein that is involved in the regulation of cell-matrix adhesion dynamics, a process required for the tumor cell migration and invasion. Phosphorylation of the serine residue 178 requires c-Jun NH2-terminal kinase (JNK) activation, which occurs downstream of epidermal growth factor receptor (EGFR)-mediated signaling and drives cell migration. In this study, we investigated the significance of paxillin Ser178 phosphorylation in breast cancer progression. Methods: We employed the rat mammary carcinoma MTLn3 cell line with which we established stabile variants of both wild type and mutant GFP-paxillin constructs. With those, we next performed several in vitro assays including cell proliferation, migration and focal adhesion dynamics. Finally, we monitored the metastatic spread of both cell line variants in an othrotopic mouse model for breast cancer. Results: Here we show that expression of the phospho-defective mutant paxillinS178A in the metastatic mammary adenocarcinoma MTLn3 cell-line significantly decreased EGF-induced cell migration, which was correlated with impaired focal adhesion dynamics. Moreover, paxillinS178A attenuated lung metastasis formation in an orthotopic in vivo mammary gland tumor/metastasis model, demonstrating the importance of JNK-mediated paxillin phosphorylation in breast cancer progression. Expression of paxillinS178A caused a decrease in EGFR expression, while re-expression of EGFR in MTLn3-paxillinS178A cells fully restored EGF-driven cell motility and focal adhesion dynamics. Furthermore, re-expression of EGFR in MTLn3-paxillinS178A rescued spontaneous metastasis from breast to lung. Conclusion: Overall our data show an important role for JNK-mediated paxillin Ser178 phosphorylation in the regulation of EGFR expression and thereby, in EGF-driven cell migration and metastasis formation.

show abstract

Paxillin actions in the nucleus

Cited by 29 publications

References 59 publications

A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis

A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis

A Polydopamine-Functionalized Carbon Microfibrous Scaffold Accelerates the Development of Neural Stem Cells

Paxillin serine 178 phosphorylation in control of cell migration and metastasis formation through regulation of EGFR expression in breast cancer

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