The p38 MAPK stress pathway as a tumor suppressor or more?

Loesch, Mathew

doi:10.2741/2951

Cited by 100 publications

(89 citation statements)

References 119 publications

(152 reference statements)

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“…p38 MAPKs consist of four family members (␣, ␤, ␥, and ␦) in which p38␣ is ubiquitously present, whereas p38␥ is highly expressed in certain cancers (3). In addition to well established regulatory effects in cytokine signaling and stress response, substantial evidence suggests that the p38␣ pathway functions as a tumor suppressor (4 -8).…”

Section: Mapksmentioning

confidence: 99%

p38γ MAPK Cooperates with c-Jun in trans-Activating Matrix Metalloproteinase 9

Loesch

Zhi

Hou

et al. 2010

Journal of Biological Chemistry

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106

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Mitogen-activated protein kinases (MAPKs) regulate gene expression through transcription factors. However, the precise mechanisms in this critical signal event are largely unknown. Here, we show that the transcription factor c-Jun is activated by p38␥ MAPK, and the activated c-Jun then recruits p38␥ as a cofactor into the matrix metalloproteinase 9 (MMP9) promoter to induce its trans-activation and cell invasion. This signaling event was initiated by hyperexpressed p38␥ that led to increased c-Jun synthesis, MMP9 transcription, and MMP9-dependent invasion through p38␥ interacting with c-Jun. p38␥ requires phosphorylation and its C terminus to bind c-Jun, whereas both c-Jun and p38␥ are required for the trans-activation of MMP9. The active p38␥/c-Jun/MMP9 pathway also exists in human colon cancer, and there is a coupling of increased p38␥ and MMP9 expression in the primary tissues. These results reveal a new paradigm in which a MAPK acts both as an activator and a cofactor of a transcription factor to regulate gene expression leading to an invasive response. MAPKs3 (including extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38s) are critical signaling cascades that convert upstream signals into biological responses such as cell proliferation, invasion, and transformation (1). MAPKs are believed to do so by phosphorylating and activating a group of transcription factors, which through binding regulatory DNA elements lead to altered gene transcription. c-Jun is a major component of the AP-1 transcription factor downstream of MAPKs, whereas AP-1 is composed of homodimers of the Jun family or its heterodimers with another transcription factor such as c-Fos to bind the consensus DNA elements TGAg/cTCA (2). c-Jun is activated by JNK through phosphorylation at Ser-63, Ser-73, Thr-91, and Thr-93, and by ERK and p38 via increased gene expression. Activated c-Jun/ AP-1 leads to a cell type-specific biological response through integrated gene expression (1). However, the exact mechanism by which c-Jun converts a MAPK activity into a target gene expression remains mostly unknown.p38 MAPKs consist of four family members (␣, ␤, ␥, and ␦) in which p38␣ is ubiquitously present, whereas p38␥ is highly expressed in certain cancers (3). In addition to well established regulatory effects in cytokine signaling and stress response, substantial evidence suggests that the p38␣ pathway functions as a tumor suppressor (4 -8). p38␥, on the other hand, is a 43-kDa protein with an unique C-terminal motif, KETXL, that can dock with the PDZ (PSD-95/Dlg/ZO-1 homology) domain of other proteins (9, 10). In contrast to p38␣, our recent studies showed that p38␥ is induced by Ras and required for Ras transformation and invasion (11, 12), indicating its oncogenic activity. The underlying mechanisms for p38␥ involvement in Ras tumorigenesis, however, have not been established. In this report, we show that p38␥ acts both as an activator and a cofactor for c-Jun in trans-activating MMP9, a critical matrix metalloprote...

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Section: Mapksmentioning

confidence: 99%

p38γ MAPK Cooperates with c-Jun in trans-Activating Matrix Metalloproteinase 9

Loesch

Zhi

Hou

et al. 2010

Journal of Biological Chemistry

Self Cite

106

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“…Phosphatidylinositol-3 kinase (PI3K) controls cell motility through the activation of protein kinase B (Akt) and other targets (19,20); however, cell-dependent differences in these regulatory mechanisms exist (18,(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

Regulation of cell migration via the EGFR signaling pathway in oral squamous cell carcinoma cells

et al. 2016

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Abstract. Cell migration potency is essential in cancer metastasis and is often regulated by extracellular stimuli. Oral squamous cell carcinoma cell lines include those that are sensitive, as well as resistant, to the effects of the epidermal growth factor receptor (EGFR) inhibitor cetuximab on cell migration. In the present study, the molecular differences in the EGFR response to cell migration between the SAS cetuximab-sensitive and HSC4 cetuximab-resistant cell lines was examined. Treatment with the EGFR inhibitors AG1478 and cetuximab reduced the migration potency of SAS cells, but not HSC4 cells. The migration of the two cell lines was inhibited under serum-free culture conditions, and the addition of EGF to the serum-free medium promoted the migration of SAS cells, but not HSC4 cells. In addition, SAS cell migration was reduced by the mitogen-activated protein kinase kinase and protein kinase B (Akt) inhibitors PD98059 and MK2206, whereas HSC4 cell migration was only inhibited by MK2206. EGF induced an increase in extracellular signal-regulated kinase phosphorylation levels in HSC4 cells, and stimulated Akt phosphorylation levels in SAS cells. Furthermore, the staining of actin filaments with phalloidin was significantly increased by the inhibition of EGFR in SAS cells, but was not observed as altered in HSC4 cells. Conversely, the addition of EGF to the culture medium decreased the accumulation of actin filaments in SAS cells. The results suggest that the EGF-EGFR signaling pathway has an important role in SAS cell migration via the modulation of actin dynamics, and that HSC4 cell migration is regulated by a serum component other than EGFR.

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“…Here, we have shown that p38␥ is selectively activated by TAM and that p38␥ activity is necessary and sufficient to stimulate ER/Ser-118 phosphorylation and to confer SERM sensitivity. Because p38␥ and p38␣ activities are antagonistic (20,24,56) and because increased p38␣ activity is involved in TAM resistance in breast cancer cells and in patients (48,57), the hyperexpression of p38␥ may be a major determinant of breast cancer hormone sensitivity, both through stimulating the ER nonclassical pathway and through antagonizing p38␣ activity.…”

Section: Discussionmentioning

confidence: 99%

“…It possess both ERKlike mitogenic and p38-like stress kinase properties (20,21). Similar to ERK, p38␥ signals downstream of Ras to increase its transforming and invasive activities (22)(23)(24)(25).…”

Section: Estrogen Receptor ␣ (Er)mentioning

confidence: 99%