MAP Kinases: From Intracellular Signals to Physiology and Disease

Schramek, Herbert

doi:10.1152/nips.01365.2001

Cited by 59 publications

(71 citation statements)

References 16 publications

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“…8 and 9). The p38 MAP kinase belongs to a subfamily of the MAP kinases and is activated primarily in response to stress, as well as cytokine stimulation (54,55). Earlier studies suggest that different subfamilies of MAP kinases play a distinct role in regulating cell apoptosis, with ERK-MAP kinase as pro-survival and p38 MAP kinase and JNK as pro-death signals (56 -58).…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-ॆ1 Potentiates Renal Tubular Epithelial Cell Death by a Mechanism Independent of Smad Signaling

Dai

Yang

Liu

2003

Journal of Biological Chemistry

137

109

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Tubular atrophy resulting from epithelial cell loss is one of the characteristic features in the development of chronic renal interstitial fibrosis. Although the trigger(s) and mechanism for tubular cell loss remain undefined, the hyperactive transforming growth factor (TGF)-␤1 signaling has long been suspected to play an active role. Here we demonstrate that although TGF-␤1 did not induce cell death per se, it dramatically potentiated renal tubular cell apoptosis initiated by other death cues in vitro. Pre-incubation of human kidney epithelial cells (HKC) with TGF-␤1 markedly promoted staurosporine-induced cell death in a time-and dose-dependent manner. TGF-␤1 dramatically accelerated the cleavage and activation of pro-caspase-9, but not procaspase-8, in HKC cells. This event was followed by an accelerated activation of pro-caspase-3. To elucidate the mechanism underlying TGF-␤1 promotion of tubular cell death, we investigated the signaling pathways activated by TGF-␤1. Both Smad-2 and p38 mitogenactivated protein (MAP) kinase were rapidly activated by TGF-␤1, as demonstrated by the early induction of phosphorylated Smad-2 and p38 MAP kinase, respectively. We found that overexpression of inhibitory Smad-7 completely abolished Smad-2 phosphorylation and activation induced by TGF-␤1 but did not inhibit TGF-␤1-induced apoptosis. However, suppression of p38 MAP kinase with chemical inhibitor SC68376 not only abolished p38 MAP kinase phosphorylation but also obliterated apoptosis induced by TGF-␤1. These results suggest that hyperactive TGF-␤1 signaling potentiates renal tubular epithelial cell apoptosis by a Smadindependent, p38 MAP kinase-dependent mechanism.

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Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-ॆ1 Potentiates Renal Tubular Epithelial Cell Death by a Mechanism Independent of Smad Signaling

Dai

Yang

Liu

2003

Journal of Biological Chemistry

137

109

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“…This choice was not arbitrary, as this pathway is one of the major downstream signalling pathways from EGFR. Activated ERK1/2 control many processes that are central to malignant progression, including cell growth, apoptosis and migration (Pages et al, 1993;Campbell et al, 1995;Hoshino et al, 1999;Schramek, 2002). Disrupting regulation of the MAPK pathway can predispose cells to undergo tumorigenic transformation, as illustrated by the position of the ras oncogene upstream of ERK (Zhang et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells

et al. 2004

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One of the major targets for breast cancer therapy is the epidermal growth factor receptor (EGFR) and related receptors, which signal via different signal transduction pathways including the mitogen-activated protein kinase (MAPK) pathway. This study determined whether there is a correlation between EGFR/HER2 status and MAPK (ERK1/2) phosphorylation in breast cancer cells, and how this affects the response to an inhibitor of the receptors. Expression of EGFR, HER2 and phosphorylated ERK1/2 were measured by immunoblotting in a panel of breast cancer cell lines. Several lines expressed high levels of pERK1/2, with no obvious correlation with the level of EGFR/HER2. The EGFR tyrosine kinase inhibitor PKI166 inhibited growth and induced apoptosis in some cells with high levels of growth factor receptors (MDA-MB-468, SUM149, SKBR3), but was less effective in cells that also had high basal ERK1/2 activity (MDA-MB-231). The combination of an inhibitor of MAPK signalling (U0126) and PKI166 produced significantly more inhibition and apoptosis than either agent alone. This suggests that constitutive activation of the MAPK pathway may bypass inhibition of EGFR/HER2 tyrosine kinases, and lead to insensitivity to agents targeting the receptors. However, inhibiting both EGFR/ HER2 and MAPK signalling can result in significant growth inhibition and apoptosis of EGFR-expressing breast cancer cells.

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“…Evidence supports the involvement of ERK1/2 in PAR-mediated cell proliferation: (i) the MEK inhibitor PD98059 abrogated cell proliferation stimulated by PAR2 agonists; and (ii) activation of PAR2 resulted in ERK1/2 phosphorylation. Whereas the relationship between ERK activation and cell proliferation is well documented (22), the mechanism by which PAR2 activates MAPKs (ERK1/2) was not known. The important finding of our study was to show that transactivation of EGF-R is an essential link between PAR2 activation and colon cancer cell proliferation.…”

Section: Effect Of Src Inhibitor On Par Agonist-induced Egf-r Phosphomentioning

confidence: 99%

Protease-activated Receptor 2 in Colon Cancer

Darmoul

Gratio

Devaud

et al. 2004

Journal of Biological Chemistry

189

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Several lines of evidence suggest that tumor-derived trypsin contributes to the growth and invasion of cancer cells. We have recently shown that trypsin is a potent growth factor for colon cancer cells through activation of the G protein-coupled receptor protease-activated receptor 2 (PAR2). Here, we analyzed the signaling pathways downstream of PAR2 activation that lead to colon cancer cell proliferation in HT-29 cells. Our data are consistent with the following cascade of events upon activation of PAR2 by the serine protease trypsin or the specific PAR2-activating peptide (AP2): (i) a matrix metalloproteinasedependent release of transforming growth factor (TGF)-␣, as demonstrated with TGF-␣-blocking antibodies and measurement of TGF-␣ in culture medium; (ii) TGF-␣-mediated activation of epidermal growth factor receptor (EGF-R) and subsequent EGF-R phosphorylation; and (iii) activation of ERK1/2 and subsequent cell proliferation. The links between these events are demonstrated by the fact that stimulation of cell proliferation and ERK1/2 upon activation of PAR2 is reversed by the metalloproteinase inhibitor batimastat, TGF-␣-neutralizing antibodies, EGF-R ligand binding domain-blocking antibodies, and the EGF-R tyrosine kinase inhibitors AG1478 and PD168393. Therefore, transactivation of EGF-R appears to be a major mechanism whereby activation of PAR2 results in colon cancer cell growth. By using the Src tyrosine kinase inhibitor PP2, we further showed that Src plays a permissive role for PAR2-mediated ERK1/2 activation and cell proliferation, probably acting downstream of the EGF-R. These data explain how trypsin exerts robust trophic action on colon cancer cells and underline the critical role of EGF-R transactivation.Proteases have been increasingly recognized as important factors in pathophysiology of tumor diseases. Besides their contribution to cancer progression by the degradation of extracellular matrix proteins, there is now substantial evidence that certain proteases serve as signal molecules controlling cell functions through specific membrane receptors, the proteaseactivated receptors. PARs 1 are seven transmembrane-spanning domain G protein-coupled receptors comprising four receptors named PAR1, PAR2, PAR3, and PAR4 (1, 2). Thrombin is the physiological activator of PAR1, PAR3, and PAR4, whereas PAR2 is activated by multiple trypsin-like enzymes including trypsin and mast cell tryptase but not thrombin. The mechanism of activation of PARs was initially established for PAR1 (3) and seems to be a paradigm for the other PARs (1, 2, 4). They are irreversibly activated by a proteolytic mechanism in which the protease binds to and cleaves the amino-terminal exodomain of the receptor. This cleavage generates a new amino-terminal sequence that binds intramolecularly to the core receptor and serves as a tethered ligand. Synthetic activating peptides that mimic the tethered ligand domains of PAR1, PAR2, and PAR4 have been developed. The activation of PARs by these synthetic peptides APs is independent of rec...

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MAP Kinases: From Intracellular Signals to Physiology and Disease

Cited by 59 publications

References 16 publications

Transforming Growth Factor-ॆ1 Potentiates Renal Tubular Epithelial Cell Death by a Mechanism Independent of Smad Signaling

Transforming Growth Factor-ॆ1 Potentiates Renal Tubular Epithelial Cell Death by a Mechanism Independent of Smad Signaling

Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells

Protease-activated Receptor 2 in Colon Cancer

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