Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinase-13 (MMP-13, or collagenase 3) has been shown to degrade intact collagen and to participate in situations where rapid and effective remodeling of collagenous ECM is required. Mechanical strain induction of MMP-13 is an example of how osteoblasts respond to high mechanical forces and participate in the bone-remodeling mechanism. Using MC3T3-E1 osteoblast-like cells, we dissected the signaling molecules involved in MMP-13 induction by mechanical strain. Reverse transcription-PCR and zymogram analysis showed that platelet-derived growth factor receptor (PDGFR) inhibitor, AG1296, inhibited the mechanical strain-induced MMP-13 gene and activity. However, the induction was not affected by anti-PDGF-AA serum. Immunoblot analysis revealed time-dependent phosphorylation of PDGFR-alpha up to 2.7-fold increases within 3 min under strain. Transfection with shPDGFR-alpha (at 4 and 8 microg/ml) abolished PDGFR-alpha and reduced MMP-13 expression. Moreover, time-dependent recruitments of phosphoinositide 3-kinase (PI3K) by PDGFR-alpha were detected by immunoprecipitation with anti-PDGFR-alpha serum followed by immunoblot with anti-PI3K serum. AG1296 inhibited PDGFR-alpha/PI3K aggregation and Akt phosphorylation. Interestingly, protein kinase C-delta (PKC-delta) inhibitor, rottlerin, inhibited not only PDGFR-alpha/PI3K aggregation but PDGFR-alpha phosphorylation. The sequential activations were further confirmed by mutants DeltaPKC-delta, DeltaAkt, and DeltaERK1. Consistently, the primary mouse osteoblast cells used the same identified signaling molecules to express MMP-13 under mechanical strain. These results demonstrate that, in osteoblast-like cells, the MMP-13 induction by mechanical strain requires the transactivation of PDGFR-alpha by PKC-delta and the cross-talk between PDGFR-alpha/PI3K/Akt and MEK/ERK pathways.
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PMID:Protein kinase C-delta transactivates platelet-derived growth factor receptor-alpha in mechanical strain-induced collagenase 3 (matrix metalloproteinase-13) expression by osteoblast-like cells. 1963 90

Advances in the treatment of breast cancer have resulted in increased survival. However, in the metastatic setting, the disease remains incurable. Therefore, understanding of the mechanisms that promote dissemination of breast cancer cells may favor the development of novel therapeutic strategies to fight those tumors. Here, we show that the ErbB ligands, Neuregulins (NRGs), promote metastatic dissemination of breast cancer cells by switching on a kinase-metalloproteinase network. Clinicopathological analyses demonstrated that NRG expression in breast tumors associated to lymph node invasion and poor patient outcome. Preclinical in vivo analyses showed that NRG expression favored in situ tumor growth, local spreading and metastatic dissemination. Genomic, biochemical and functional studies identified matrix metalloproteinases, particularly stromelysin 2 and collagenase 3, as key mediators of the NRG-induced dissemination properties of breast cancer cells. Mechanistic analyses demonstrated that NRG augmented metalloproteinase expression through a route controlled by ERK1/2 kinases. ERK1/2 increased collagenase 3 expression by controlling the activity of an SBF1-related transcription factor. In conclusion, we describe a pathway linked to breast cancer dissemination. The clinical availability of agents that target some of the components of this signalling pathway suggests that patients with tumors fed by NRGs or other factors able to activate the ERK-Collagenase 3 route may benefit from agents that act on that signalling axis.
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PMID:Breast cancer dissemination promoted by a neuregulin-collagenase 3 signalling node. 2636 98