Paxillin phosphorylation by <scp>JNK</scp> and p38 is required for <scp>NFAT</scp> activation

Lee, Yu‐Chi; Chang, An-Yun; Lin-Feng, Ming-Hsien; Tsou, Wen-I; Chiang, I-Hsuan; Lai, Ming‐Zong

doi:10.1002/eji.201142192

Cited by 9 publications

(10 citation statements)

References 43 publications

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“…Recent studies of cell migration showed that serine phosphorylation of paxillin was mediated by JNK and that p38 MAPK was crucial for this cellular process [30, 31]. …”

Section: Discussionmentioning

confidence: 99%

Reversibility of regorafenib effects in hepatocellular carcinoma cells

D’Alessandro

Refolo

Lippolis

et al. 2013

Cancer Chemother Pharmacol

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Purpose Multikinase growth inhibitors inhibit their target kinases with varying potency. Patients often require lower doses or therapy breaks due to drug toxicities. To evaluate the effects of drug withdrawal on hepatocellular carcinoma cells after incubation with growth-inhibitory concentrations of regorafenib, cell growth, migration and invasion, and signaling were examined. Methods Cell proliferation, motility, and invasion were analyzed by MTT, wound healing, and invasion assays, respectively, and MAPK pathway protein markers were analyzed by Western blot. Results After regorafenib removal, cell growth, migration, and invasion recovered. Repeated drug exposure resulted in changes in cell growth patterns. Recovery could be blocked by sub-growth-inhibitory concentrations of either doxorubicin or vitamin K1. Recovery of growth was associated with increased phospho-JNK, phospho-p38, and phospho-STAT3 levels. The recovery of growth, migration, and signaling were blocked by a JNK inhibitor. Conclusions Removal of regorafenib from growth-inhibited cells resulted in a JNK-dependent recovery of growth and migration.

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“…Recent studies of cell migration showed that serine phosphorylation of paxillin was mediated by JNK and that p38 MAPK was crucial for this cellular process [30, 31]. …”

Section: Discussionmentioning

confidence: 99%

Reversibility of regorafenib effects in hepatocellular carcinoma cells

D’Alessandro

Refolo

Lippolis

et al. 2013

Cancer Chemother Pharmacol

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“…S1C). These cytoskeletal JNK substrate proteins include those associating with microtubules (DCX [260][261][262], MAP1B [180,263], MAP2 [264], Tau [265], and WDR62 [213]), the actin cytoskeleton (MARCKSL1 [266] and SMTL2 [267]), or focal adhesions (paxillin [268,269] and ␤-catenin [270][271][272]). In addition, JNK-mediated phosphorylation of additional proteins may also direct vesicular transport (through phosphorylation of JIP1 and ␤-APP [104,217]), as well as the exocytosis of specialized, Glut4-containing vesicles (through insulin-stimulated phosphorylation of IRS1 and IRS2 [273,274]).…”

Section: Major Classes Of Proteins Targeted By Jnksmentioning

confidence: 99%

“…One of the better-characterized substrates is the focal adhesion protein paxillin. Although paxillin has been implicated as an ERK2-dependent target, it can also be phosphorylated (at least on Ser 178) by JNK (268,269). Paxillin displays an intriguing interplay between Ser/Thr and Tyr phosphorylation.…”

Section: Jnk Phospho-switches Potentiating New Protein-protein Bindinmentioning

confidence: 99%

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Zeke

Misheva

Reményi

et al. 2016

Microbiol Mol Biol Rev

383

350

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SUMMARYThe c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.

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“…6,12,41 Various studies have shown that pJNK can be a kinase for Ser 178 of paxillin. 7,42 Our in-vitro kinase screening assay (data unpublished) with a panel of 229 kinases shows that JNK is a relatively powerful kinase for recombinant human paxillin substrate.…”

Section: Hypothesismentioning

confidence: 98%

“…These potential phosphorylation sites are targeted by various kinases activated by adhesion signaling and growth factors. [6][7][8][9] The role of phosphorylation in adhesion complex signaling is relatively less understood compared with other conventional signaling paradigms and kinase cascades.…”

Section: Role Of Paxillin In Cell Adhesionmentioning

confidence: 99%