Activation of the Pro-survival Phosphatidylinositol 3-Kinase/AKT Pathway by Transforming Growth Factor-β1 in Mesenchymal Cells Is Mediated by p38 MAPK-dependent Induction of an Autocrine Growth Factor

Horowitz, Jeffrey C.; Lee, Daniel Y.; Waghray, Meghna; Keshamouni, Venkateshwar G.; Thomas, Peedikayil E.; Zhang, Hengmin; Cui, Zongbin; Thannickal, Victor J.

doi:10.1074/jbc.m306248200

Cited by 217 publications

(237 citation statements)

References 50 publications

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“…Normal primary human fetal lung fibroblasts (IMR-90; Institute for Medical Research, Camden, NJ, USA) were cultured as previously described [8] and studies performed at passage 5-9. Cells were plated on cell culture dishes or on 96-well cell culture plates and incubated with DMEM containing 10% fetal bovine serum (FBS) in 5% CO 2 -95% air.…”

Section: Cell Culturementioning

confidence: 99%

“…Cell lysates were prepared in RIPA buffer and subjected to SDS-PAGE and Western blot analyses performed as described previously [8].…”

Section: Western Immunoblottingmentioning

confidence: 99%

“…Assays for apoptosis/anoikis 2.6.1. ELISA for ssDNA-This assay is based on the susceptibility of double-stranded DNA in apoptotic cells to form single strands when exposed to formamide [23] and was performed as previously described [8].…”

Section: Western Immunoblottingmentioning

confidence: 99%

“…In epithelial cells, TGF-β1 typically functions as a tumour-suppressor through growth-inhibition, cell-cycle arrest and induction of apoptosis [2]. In contrast, TGF-β1 promotes mesenchymal cell proliferation and survival [3][4][5][6][7][8]. These opposing actions on epithelial and mesenchymal cells favour net loss of epithelial cells and accumulation of myofibroblasts in injured tissues, a hallmark of human fibrotic diseases [9].…”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown that TGF-β1 protects myofibroblasts from serum deprivationinduced apoptosis through activation of the PI3K-AKT pathway via the p38 MAPK-dependent secretion of an autocrine growth factor [8]. This study was undertaken to determine the regulatory mechanisms of FAK and AKT by TGF-β1 via SMAD-dependent and -independent pathways, the potential interdependence of these pro-survival protein kinase pathways and their role(s) in the protection of myofibroblasts from anoikis.…”

Section: Introductionmentioning

confidence: 99%

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Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

Horowitz

Rogers

Sharma

et al. 2007

Cellular Signalling

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222

177

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Transforming growth factor-β (TGF-β) is a prototypical tumour-suppressor cytokine with cytostatic and pro-apoptotic effects on most target cells; however, mechanisms of its pro-survival/antiapoptotic signalling in certain cell types and contexts remain unclear. In human lung fibroblasts, TGF-β1 is known to induce myofibroblast differentiation in association with the delayed activation of focal adhesion kinase (FAK) and protein kinase B (PKB/AKT). Here, we demonstrate that FAK and AKT are independently regulated by early activation of SMAD3 and p38 MAPK, respectively. Pharmacologic or genetic approaches that disrupt SMAD3 signalling block TGF-β1-induced activation of FAK, but not AKT; in contrast, disruption of early p38 MAPK signalling abrogates AKT activation, but does not alter FAK activation. TGF-β1 is able to activate AKT in cells expressing mutant FAK or in cells treated with an RGD-containing peptide that interferes with integrin signalling, inhibits FAK activation and induces anoikis (apoptosis induced by loss of adhesion signalling). TGF-β1 protects myofibroblasts from anoikis, in part, by activation of the PI3K-AKT pathway. Thus, TGF-β1 co-ordinately and independently activates the FAK and AKT protein kinase pathways to confer an anoikis-resistant phenotype to myofibroblasts. Activation of these prosurvival/anti-anoikis pathways in myofibroblasts likely contributes to essential roles of TGF-β1 in tissue fibrosis and tumour-promotion.

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Section: Cell Culturementioning

confidence: 99%

“…Cell lysates were prepared in RIPA buffer and subjected to SDS-PAGE and Western blot analyses performed as described previously [8].…”

Section: Western Immunoblottingmentioning

confidence: 99%

Section: Western Immunoblottingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

Horowitz

Rogers

Sharma

et al. 2007

Cellular Signalling

Self Cite

222

177

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IL‐8 increases integrin expression and cell motility in human chondrosarcoma cells

Lee

Huang

Chen

et al. 2011

J of Cellular Biochemistry

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Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. Interleukin-8 (IL-8), a chemokine with a defining CXC amino acid motif, is known to possess tumorigenic and proangiogenic properties. Over-expression of IL-8 has been detected in many human tumors. However, the effects of IL-8 in migration and integrin expression in chondrosarcoma cells are largely unknown. In this study, we found that IL-8 increased the migration and the expression of αvβ3 integrin in human chondrosarcoma cells. Activations of phosphatidylinositol 3-kinase (PI3K), Akt, and AP-1 pathways after IL-8 treatment were demonstrated, and IL-8-induced expression of integrin and migration activity was inhibited by the specific inhibitor and mutant of PI3K, Akt, and AP-1 cascades. Taken together, our results indicated that IL-8 enhances the migration of chondrosarcoma cells by increasing αvβ3 integrin expression through the PI3K/Akt/AP-1 signal transduction pathway.

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Macrophage migration inhibitory factor increases cell motility and up‐regulates αvβ3 integrin in human chondrosarcoma cells

Lee¹,

Su²,

Huang³

et al. 2012

J of Cellular Biochemistry

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The macrophage migration-inhibitory factor (MIF) is a pro-inflammatory cytokine first known for its effect on macrophage migration and activation. Recent studies have shown that MIP plays a critical role in tumor growth, angiogenesis, and metastasis. Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. However, the effects of MIF on human chondrosarcoma cells are largely unknown. In the present study, MIF was found to increase the migration and the expression of αvβ3 integrin in human chondrosarcoma cells. The phosphatidylinositol 3-kinase (PI3K), Akt, and NF-κB pathways were activated by MIF treatment, and the MIF-induced expression of integrin and migration activity were inhibited by the specific inhibitors and mutant forms of PI3K, Akt, and NF-κB cascades. In addition, migration-prone sublines demonstrated that increased cell migration ability was correlated with increased expression of MIF and αvβ3 integrin. Taken together, our results indicate that MIF enhanced the migration of the chondrosarcoma cells by increasing αvβ3 integrin expression through the PI3K/Akt/NF-κB signal transduction pathway.

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Activation of the Pro-survival Phosphatidylinositol 3-Kinase/AKT Pathway by Transforming Growth Factor-β1 in Mesenchymal Cells Is Mediated by p38 MAPK-dependent Induction of an Autocrine Growth Factor

Cited by 217 publications

References 50 publications

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

IL‐8 increases integrin expression and cell motility in human chondrosarcoma cells

Macrophage migration inhibitory factor increases cell motility and up‐regulates αvβ3 integrin in human chondrosarcoma cells

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