Regulation of Raf-Akt Cross-talk

Moelling, Karin; Schad, Karen; Bosse, Magnus; Zimmermann, Sven; Schweneker, Marc

doi:10.1074/jbc.m111974200

Cited by 359 publications

(324 citation statements)

References 43 publications

Supporting

Mentioning

277

Contrasting

Unclassified

Order By: Relevance

“…The finding that IL-1β stimulated the phosphorylation of ERK but not Akt would also be consistent with this, since IL-1 is known to be a potent inhibitor of proteoglycan synthesis [28,29]. The mechanism by which ERK activity might inhibit IGF-I-stimulated proteoglycan synthesis is not clear but could involve a negative feedback loop through ERK-mediated serine phosphorylation of IRS-1, which has been shown to inhibit insulin signalling [30,31]. Further studies will be necessary to determine whether this mechanism contributes to inhibition of IGF-I signalling in chondrocytes.…”

Section: Discussionsupporting

confidence: 54%

IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK

Starkman

Cravero

DelCarlo

et al. 2005

Biochemical Journal

159

161

View full text Add to dashboard Cite

The IGF-I (insulin-like growth factor-I) signalling pathway responsible for regulation of proteoglycan synthesis in chondrocytes has not been defined and is the focus of the present study. Chondrocytes isolated from normal human articular cartilage were stimulated with IGF-I in monolayer culture or in suspension in alginate. IGF-I activated members of both the PI3K (phosphoinositide 3-kinase) pathway and the ERK (extracellular-signal-regulated kinase)/MAPK (mitogen-activated protein kinase) pathway. The PI3K inhibitors LY294002 and wortmannin blocked IGF-I-stimulated Akt phosphorylation without blocking ERK phosphorylation and this was associated with complete inhibition of proteoglycan synthesis. A decrease in IGF-I-stimulated proteoglycan synthesis was also observed upon inhibition of mTOR (mammalian target of rapamycin) and p70S6 kinase, both of which are downstream of Akt. The MEK (MAPK/ERK kinase) inhibitors PD98059 and U0126 blocked IGF-I-stimulated ERK phosphorylation but did not block the phosphorylation of Akt and did not decrease proteoglycan synthesis. Instead, in alginate- cultured chondrocytes, the MEK inhibitors increased IGF-I-stimulated proteoglycan synthesis when compared with cells treated with IGF-I alone. This is the first study to demonstrate that IGF-I stimulation of the PI3K signalling pathway is responsible for the ability of IGF-I to increase proteoglycan synthesis. Although IGF-I also activates the ERK/MAPK pathway, ERK activity is not required for proteoglycan synthesis and may serve as a negative regulator

show abstract

Section: Discussionsupporting

confidence: 54%

IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK

Starkman

Cravero

DelCarlo

et al. 2005

Biochemical Journal

159

161

View full text Add to dashboard Cite

show abstract

“…Furthermore this was accompanied by definite inhibition of ERK activation, not only in cells expressing or overexpressing WT B-RAF, but also, unexpectedly, in cells that had been transfected with V600E B-RAF (Figure 4b). We hypothesize that ERK phosphorylation may be inhibited, despite continued expression of activated B-RAF, as a result of cross-talk from the PI3K-Akt pathway IGF1R targeting in V600E B-RAF melanoma AH Yeh et al (Moelling et al, 2002). Consistent with this, 3-phosphoinositide-dependent protein kinase-1 (PDK1) has been shown to phosphorylate the activation loop of MEK1/2 (Sato et al, 2004).…”

Section: Igf1r Targeting In V600e B-raf Melanomamentioning

confidence: 83%

Human melanoma cells expressing V600E B-RAF are susceptible to IGF1R targeting by small interfering RNAs

2006

View full text Add to dashboard Cite

The type 1 insulin-like growth factor receptor (IGF1R) is overexpressed by malignant melanomas compared with benign naevi, and mediates proliferation, motility and protection from apoptosis. However, the utility of IGF1R targeting as anti-cancer therapy may be limited by activating mutations in downstream signaling intermediates. We previously showed that IGF1R knockdown blocked survival of prostate cancer cells in which Akt activation was deregulated by PTEN loss. The current study investigated effects of IGF1R targeting in cells harboring activating RAS-RAF mutations, found in 70-80% of human melanomas. We assembled a panel of eight human melanoma cell lines: two expressing wild-type (WT) B-RAF and N-RAS, two with activating N-RAS mutations and four harboring V600E B-RAF. We also generated isogenic cell populations overexpressing WT or V600E B-RAF. Cells expressing V600E B-RAF were relatively resistant to apoptosis. However, IGF1R gene silencing was capable of inducing significant inhibition of survival, enhancement of apoptosis, and Btwo-fold sensitization to cisplatin and temozolomide. These effects were independent of mutation status and were associated with reduced activation of Akt and also, unexpectedly, of ERKs. These results support development of IGF1R targeting as therapy for melanoma, regardless of the presence of activating mutations in the RAS-RAF pathway.

show abstract

“…HDACis, which are known differentiating compounds, restore the normal gene expression of cancer cells by altering transcription levels of cell cycle regulatory proteins; they induce the expression of the antiproliferative gene p21, regulate the activity of the tumor suppressor p53, and reduce the expression of positive regulators of proliferation, such as cyclin D1, c-myc and c-Src [17,18]. The PKC activator PMA directly induces the Raf-MEK-ERK signaling pathyway, that further activates the cellcycle inhibitor p21 and diminishes cell growth [61]. During HDACi-or PMA-induced differentiation we found marked PMCA4b upregulation both at the mRNA and protein levels, while there were no significant changes in the expression of the other PMCA isoforms.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitor- and PMA-induced upregulation of PMCA4b enhances Ca2+ clearance from MCF-7 breast cancer cells

et al. 2014

View full text Add to dashboard Cite

The expression of the plasma membrane Ca 2+ ATPase (PMCA) isoforms is altered in several types of cancer cells suggesting that they are involved in cancer progression. In this study we induced differentiation of MCF-7 breast cancer cells by histone deacetylase inhibitors (HDACis) such as short chain fatty acids (SCFAs) or suberoylanilide hydroxamic acid (SAHA), and by phorbol 12-myristate 13-acetate (PMA) and found strong upregulation of PMCA4b protein expression in response to these treatments. Furthermore, combination of HDACis with PMA augmented cell differentiation and further enhanced PMCA4b expression both at mRNA and protein levels. Immunocytochemical analysis revealed that the upregulated protein was located mostly in the plasma membrane. To examine the functional consequences of elevated PMCA4b expression, the characteristics of intracellular Ca 2+ signals were investigated before and after differentiation inducing treatments, and also in cells overexpressing PMCA4b. The increased PMCA4b expression -either by treatment or overexpression -led to enhanced Ca 2+ clearance from the stimulated cells. We found pronounced PMCA4 protein expression in normal breast tissue samples highlighting the importance of this pump for the maintenance of mammary epithelial Ca 2+ homeostasis. These results suggest that modulation of Ca 2+ signaling by enhanced PMCA4b expression may contribute to normal development of breast epithelium and may be lost in cancer.3

show abstract

Regulation of Raf-Akt Cross-talk

Cited by 359 publications

References 43 publications

IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK

IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK

Human melanoma cells expressing V600E B-RAF are susceptible to IGF1R targeting by small interfering RNAs

Histone deacetylase inhibitor- and PMA-induced upregulation of PMCA4b enhances Ca2+ clearance from MCF-7 breast cancer cells

Contact Info

Product

Resources

About