AMOTL2 restrains transforming growth factor‐β1‐induced proliferation and extracellular matrix deposition of airway smooth muscle cells via the down‐regulation of YAP1 activation

Abstract

Angiomotin‐like 2 (AMOTL2) is a key modulator of signaling transduction and participates in the regulation of various cellular progresses under diverse physiological and pathological conditions. However, whether AMOTL2 participates in asthma pathogenesis has not been fully studied. In the present work, we studied the possible role and mechanism of AMOTL2 in regulating transforming growth factor‐β1 (TGF‐β1)‐induced proliferation and extracellular matrix (ECM) deposition of airway smooth muscle (ASM) cells. Our results showed marked reductions in the abundance of AMOTL2 in TGF‐β1‐stimulated ASM cells. Cellular functional investigations confirmed that the up‐regulation of AMOTL2 dramatically decreased the proliferation and ECM deposition induced by TGF‐β1 in ASM cells. In contrast, the depletion of AMOTL2 exacerbated TGF‐β1‐induced ASM cell proliferation and ECM deposition. Further research revealed that the overexpression of AMOTL2 restrained the activation of Yes‐associated protein 1 (YAP1) in TGF‐β1‐stimulated ASM cells. Moreover, the reactivation of YAP1 markedly reversed AMOTL2‐mediated suppression of TGF‐β1‐induced ASM cell proliferation and ECM deposition. Together, these findings suggest that AMOTL2 restrains TGF‐β1‐induced proliferation and ECM deposition of ASM cells by down‐regulating YAP1 activation.

Cysteine and glycine‐rich protein 2 retards platelet‐derived growth factor‐BB‐evoked phenotypic transition of airway smooth muscle cells by decreasing YAP/TAZ activity

“…The dephosphorylation of YAP and TAZ, along with the upregulation of their nuclear localization, resulted in increased proliferation and migration of ASMCs 21,23 . Several recent studies have demonstrated that the deactivation of YAP can reverse the phenotypic switching of ASMCs that is triggered by either transforming growth factor‐β‐ or tumor necrosis factor‐α 24,26,43 . Therefore, it is imperative to ascertain the regulatory mechanism of YAP/TAZ that underlies the phenotypic switching of ASMCs during the process of asthmatic airway remodeling.…”

“…21,23 Several recent studies have demonstrated that the deactivation of YAP can reverse the phenotypic switching of ASMCs that is triggered by either transforming growth factor-β-or tumor necrosis factor-α. 24,26,43 Therefore, it is imperative to ascertain the regulatory mechanism of YAP/TAZ that underlies the phenotypic switching of ASMCs during the process of asthmatic airway remodeling. CRSP2 has significant impacts on focal adhesions and cytoskeletons, which in turn affect the activation of YAP/TAZ.…”

“…21,23 Reverting the phenotypic switch of ASMCs towards an asthmatic phenotype by inhibiting YAP/TAZ has become an attractive research focus regarding the potential application in the treatment of asthma. [24][25][26] Therefore, understanding the regulatory mechanism of YAP/TAZ underlying airway remodeling in asthma is imperative.…”

“…The dephosphorylation of YAP and TAZ and the induction of their nuclear localization accelerate the proliferation and migration of ASMCs, contributing to airway remodeling in asthma 21,23 . Reverting the phenotypic switch of ASMCs towards an asthmatic phenotype by inhibiting YAP/TAZ has become an attractive research focus regarding the potential application in the treatment of asthma 24–26 . Therefore, understanding the regulatory mechanism of YAP/TAZ underlying airway remodeling in asthma is imperative.…”

JNJ0966 inhibits PDGF-BB-induced airway smooth muscle cell proliferation and extracellular matrix production by regulating MMP-9

“…33 AMOTL2 reduces YAP1 expression to repress TGF-β1-mediated proliferation and ECM generation in ASMCs. 34 Eosinophils facilitate ASMC proliferation and ECM production through upregulating WNT-5a and TGF-β1 in asthma. 35 In this study, we found that JNJ0966 relieved the ECM deposition in PDGF-BB-induced ASMCs.…”