Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the role of c-FLIP in the motility of HeLa cells. A small interfering RNA (siRNA) directed against c-FLIP inhibited the adhesion and motility of the cells without affecting their growth rate. The long form of c-FLIP (c-FLIPL), but not the short form (c-FLIPS), enhanced adhesion and motility. Downregulation of c-FLIPL with siRNA decreased phosphorylation of FAK and ERK, while overexpression of c-FLIPL increased their phosphorylation. Overexpression of FAK activated ERK, and enhanced the motility of HeLa cells. FRNK, an inhibitory fragment of FAK, inhibited ERK and decreased motility. Inhibition of ERK also significantly suppressed c-FLIPL-promoted motility. Inhibition of ROCK by Y27632 suppressed the c-FLIPL-promoted motility by reducing phosphorylation of FAK and ERK. Overexpression of c-FLIPL increased the expression and secretion of MMP-9, and inhibition of MMP-9 by Ilomastat reduced c-FLIPL- promoted cell motility. A caspase-like domain (amino acids 222-376) was found to be necessary for the c-FLIPL-promoted cell motility. We conclude that c-FLIPL promotes the motility of HeLa cells by activating FAK and ERK, and increasing MMP-9 expression.
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PMID:C-FLIP promotes the motility of cancer cells by activating FAK and ERK, and increasing MMP-9 expression. 1841 15

Hyaluronic acid (HA) is known to play an important role in motility of tumor cells. However, the molecular mechanisms associated with HA-promoted melanoma cell motility are not fully understood. Treatment of cells with HA was shown to increase the production of reactive oxygen species (ROS) in a CD44-dependent manner. Antioxidants, such as N-acetyl-l-cysteine and seleno-l-methionine, prevented HA from enhancing cell motility. Protein kinase C (PKC)-alpha and PKCdelta were responsible for increased Rac1 activity, production of ROS, and mediated HA-promoted cell motility. HA increased Rac1 activity via CD44, PKCalpha, and PKCdelta. Transfection with dominant negative and constitutive active Rac1 mutants demonstrated that Rac1 was responsible for the increased production of ROS and cell motility by HA. Inhibition of NADPH oxidase by diphenylene iodonium and down-regulation of p47Phox and p67Phox decreased the ROS level, suggesting that NADPH oxidase is the main source of ROS production. Rac1 increased phosphorylation of FAK. FAK functions downstream of and is necessary for HA-promoted cell motility. Secretion and expression of MMP-2 were increased by treatment with HA via the action of PKCalpha, PKCdelta, and Rac1 and the production of ROS and FAK. Ilomastat, an inhibitor of MMP-2, exerted a negative effect on HA-promoted cell motility. HA increased interaction between CD44 and epidermal growth factor receptor (EGFR). AG1478, an inhibitor of EGFR, decreased phosphorylation of PKCalpha, PKCdelta, and Rac1 activity and suppressed induction of p47Phox and p67Phox. These results suggest that CD44-EGFR interaction is necessary for HA-promoted cell motility by regulating PKC signaling. EGFR-Akt interaction promoted by HA was responsible for the increased production of ROS and HA-promoted cell motility. In summary, HA promotes CD44-EGFR interaction, which in turn activates PKC signaling, involving Akt, Rac1, Phox, and the production of ROS, FAK, and MMP-2, to enhance melanoma cell motility.
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PMID:CD44-epidermal growth factor receptor interaction mediates hyaluronic acid-promoted cell motility by activating protein kinase C signaling involving Akt, Rac1, Phox, reactive oxygen species, focal adhesion kinase, and MMP-2. 1857 17