Mitogen-activated protein kinase (MAPK) pathways constitute a large modular network that regulates a variety of physiological processes, such as cell growth, differentiation, and apoptotic cell death. The function of the ERK pathway has been depicted as survival-promoting, in essence by opposing the proapoptotic activity of the stress-activated c-Jun NH(2)-terminal kinase (JNK)/p38 MAPK pathways. However, recently published work suggests that extracellular regulated kinase (ERK) pathway activity is suppressed by JNK/p38 kinases during apoptosis induction. In this review, we will summarize the current knowledge about JNK/p38-mediated mechanisms that negatively regulate the ERK pathway. In particular, we will focus on phosphatases (PP2A, MKPs) as inhibitors of ERK pathway activity in regulating apoptosis. A model proposed in this review places the negative regulation of the ERK pathway in a central position for the cellular decision-making process that determines whether cells will live or die in response to apoptosis-promoting signals. In addition, we will discuss the potential functional relevance of negative regulation of ERK pathway activity, for physiological and pathological conditions (e.g., cellular transformation).

Matrix metalloproteinases (MMPs) play an important role in the pathogenesis of disorders in which excessive degradation of extracellular matrix (ECM) occurs, such as rheumatoid arthritis, osteoarthritis, autoimmune blistering skin diseases, and tumor cell invasion and metastasis (44). The MMP gene family consists of at least 20 structurally related zinc-dependent neutral endopeptidases, collectively capable of degrading essentially all components of the ECM. According to their substrate specificities and structure, MMPs are often divided into subgroups of collagenases, stromelysins, gelatinases, membranetype MMPs, and other MMPs (25, 52). Collagenase 1 (henceforth designated MMP-1) is expressed by several types of normal and malignant cells, and it is one of the few proteolytic enzymes capable of degrading native fibrillar collagens. Increased expression of MMP-1 has been shown to correlate with poor prognosis of malignant tumors, including gastric and colon carcinomas (22,35).MMP-1 gene expression is stimulated at the transcriptional level by various growth factors, cytokines, and tumor promoters via a promoter segment located between Ϫ95 to Ϫ72 bp upstream of the transcription initiation site, which contains adjacent binding sites for AP-1 and ETS transcription factors (52, 54). The expression and transactivation capacities of AP-1 and ETS transcription factors are regulated by mitogen-activated protein kinase (MAPK) pathways, a large network of signaling modules activated by a variety of stimuli (17, 28). Three distinct MAPK pathways have been characterized in detail: extracellular signal-regulated kinase 1 (ERK1)/ERK2 (designated ERK1,2), c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38. The ERK1,2 pathway (Raf3MEK1,23ERK1,2) is activated by mitogens via Ras and by phorbol esters via protein kinase C. The stress-activated MAPK pathways JNK/SAPK (MEK kinase 1,33MAPK kinase 4,7 [MKK4,7]3JNK1,2,3) and p38 (MAPK kinase kinase [MAPKKK]3MKK3,63p38␣,␤,␥,␦) are activated by cellular stress, e.g., UV light, osmotic and oxidative stress, and inflammatory cytokines (17,28). The activation of MAPKs requires phosphorylation of conserved tyrosine and threonine residues by dualspecificity MAPK kinases, which in turn are activated by phosphorylation of two serine residues by upstream MAPKKKs. Phosphorylation of MAPKs results in their translocation to the nucleus, where they activate transcription factors by phosphorylation. Activity of MAPK kinases and MAPKs is inhibited by dephosphorylation of the regulatory serine, threonine, and tyrosine residues by serine/threonine, tyrosine, and dual-specificity phosphatases, respectively (see reference 26). Serine/ threonine protein phosphatase 1 (PP1) and PP2A inhibit the * Corresponding author. Mailing address: