The PTEN tumor suppressor inhibits human airway smooth muscle cell migration

Abstract

Abstract. Airway remodeling in asthma is characterized by increased airway smooth muscle (ASM) mass, accompanied by cell migration. It is well known that the proliferation and migration of ASM cells (ASMCs) play a key role in airway remodeling, but the precise mechanism modulating these cellular events remains unclear. One of the genes most likely to be involved in this process is the phosphatase and tensin homolog (PTEN) gene, whose deletion from chromosome 10 can inhibit the proliferation and migration of many cell types. In this study, we investigated the effects of PTEN on human ASMCs. The cells were infected with recombinant adenovirus containing wild-type PTEN cDNA (Ad-PTEN), and the results were compared with those from the uninfected cells and those infected with the GFP-labeled adenovirus vector. Cell proliferation was measured using the MTT method. Cell migration was determined by wound-healing and transwell assays. The expressions of PTEN, phospho-Akt, Akt, phospho-ERK 1/2 , ERK 1/2 , phospho-focal adhesion kinase (FAK) and FAK, were examined by Western blot analysis. The results show that PTEN is expressed endogenously in ASMCs, and that Ad-PTEN inhibits the proliferation and migration of these cells. In addition, the Ad-PTEN treatment decreased the phosphorylation of Akt and FAK but not that of ERK 1/2 . In conclusion, this study demonstrates that PTEN overexpression inhibits the proliferation and migration of human ASMCs by down-regulating the activity of the Akt and FAK signaling pathways.

Crosstalk Between Signaling Pathways Involved in the Regulation of Airway Smooth Muscle Cell Hyperplasia

“…Various signaling molecules including FAK, PI3K, PTEN, ERK, p38, Src, Rho kinase, c-Abl, and Wnt/β-catenin have been reported to be involved in the regulation of ASM cell migration in response to migratory stimuli (Parameswaran et al, 2002; Parameswaran et al, 2004; Lan et al, 2010; Cleary et al, 2014; Fang et al, 2017). However, the exact regulatory mechanism involved remains unclear.…”

“…FAK, a nRTK, has been recognized as the key signaling molecule implicated in integrin pathways which are known to regulate cytoskeletal organization during cell migration. FAK regulates ASM migration through its interaction with several signaling molecules including PI3K, Src and Rho kinase (Parameswaran et al, 2002; Parameswaran et al, 2004; Lan et al, 2010; Zhao and Guan, 2011; Cleary et al, 2014; Fang et al, 2017). Furthermore, FAK is reported to be co-regulated with phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ), a product of the PI3K signaling molecule, through PTEN.…”

“…Overexpression of PTEN dephosphorylates both PIP 3 and FAK, hence significantly inhibiting ASM migration. This suggests that PTEN may not only be involved in the regulation of ASM cell proliferation, but also in the regulation of ASM cell migration (Tamura et al, 1999; Lan et al, 2010).…”