Reversion-inducing cysteine-rich protein with Kazal motifs interferes with epidermal growth factor receptor signaling

Abstract

The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene had been isolated as an antagonist to RAS signaling; however, the mechanism of its action is not clear. In this study, the effect of loss of RECK function was assessed in various ways and cell systems. Successive cell cultivation of mouse embryonic fibroblasts (MEFs) according to 3T3 protocol revealed that the germline knockout of RECK confers accelerated cell proliferation and early escape from cellular senescence associated with downregulation of p19Arf , Trp53 and p21 Cdkn1a. In contrast, short hairpin RNA-mediated depletion of RECK induced irreversible growth arrest along with several features of the Arf, Trp53 and Cdkn1a-dependent cellular senescence. Within 2 days of RECK depletion, we observed a transient increase in protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) phosphorylation associated with an upregulated expression of cyclin D1, p19 Arf , Trp53, p21Cdkn1a and Sprouty 2. On further cultivation, RAS, AKT and ERK activities were then downregulated to a level lower than control, indicating that RECK depletion leads to a negative feedback to RAS signaling and subsequent cellular senescence. In addition, we observed that epidermal growth factor receptor (EGFR) activity was transiently upregulated by RECK depletion in MEFs, and continuously downregulated by RECK overexpression in colon cancer cells. These findings indicate that RECK is a novel modulator of EGFR signaling.

Histone deacetyltransferase inhibitors Trichostatin A and Mocetinostat differentially regulate MMP9, IL-18 and RECK expression, and attenuate Angiotensin II-induced cardiac fibroblast migration and proliferation

“…38 Since RECK has been shown to bind the ligand binding IL-6R and gp130, the signal transducing subunit of the IL-6 receptor heterodimer, 39 it may interfere with IL-6 signaling by blocking IL-6 interaction with the IL-6R/gp130 heterodimer. RECK also blocks Epidermal Growth Factor Receptor transactivation, 40 which is known to contribute to CF proliferation. 41 Thus, it is possible that HDAC inhibitors can blunt cardiac fibrosis and adverse remodeling through two different mechanisms: that is, by directly targeting MMP9 and IL-18 induction, and indirectly by restoring RECK expression.…”

Reversion-inducing cysteine-rich protein with Kazal motif (RECK) expression: an independent prognostic marker of survival in colorectal cancer

“…It also seems to be possible that RECK also regulates other signaling molecules and pathways included in angiogenesis [38]. Kitajima et al [39] identified epidermal growth factor receptor/rat sarcoma signaling as one of those pathways that are influenced by RECK. Takeuchi et al [29] have shown an inverse correlation between the RECK level and the level of vascular endothelial growth factor expression and suggested suppression of angiogenesis by limiting vascular endothelial growth factor availability.…”

A distinct function of the retinoblastoma protein in the control of lipid composition identified by lipidomic profiling

“…MEFs were isolated from littermate wild type, Rb −/− embryos and Srebf1 −/− embryos as described previously, 57 and maintained in α modified Eagle’s medium (MEMα, #135-15175, Wako, Osaka, Japan) supplemented with 10% fetal bovine serum and 1% phosphatidylserine.…”