Regulation of PHLDA1 Expression by JAK2-ERK1/2-STAT3 Signaling Pathway

Abstract

Toll-like receptor 2 (TLR2)-mediated signaling cascades and gene regulation are mainly involved in diseases, such as immunity and inflammation. In this study, microarray analysis was performed using bone marrow-derived macrophages (BMDM) and Raw 264.7 cells to identify novel proteins involved in the TLR2-mediated cellular response. We found that pleckstrin homology-like domain family, member 1 (PHLDA1) is a novel gene up-regulated by TLR2 stimulation and determined the unique signaling pathway for its expression. Treatment with TLR2 agonist Pam3 CSK4 increased mRNA, protein, and fluorescence staining of PHLDA1. Induction of PHLDA1 by TLR2 stimulation disappeared from TLR2 KO mice-derived BMDM. Among janus kinase (JAK) family members, JAK2 was involved in TLR2-stimulated PHLDA1 expression. Signal transducer and activator of transcription 3 (STAT3) also participated in PHLDA1 expression downstream of the JAK2. Interestingly, ERK1/2 was an intermediate between JAK2 and STAT3. In silico analysis revealed the presence of highly conserved γ-activated sites within mouse PHLDA1 promoter and confirmed the JAK2-STAT3 pathway is important to Pam3 CSK4 -induced PHLDA1 transcription. These findings suggest that the JAK2-ERK1/2-STAT3 pathway is an important signaling pathway for PHLDA1 expression and that these proteins may play a critical role in eliciting TLR2-mediated immune and inflammatory response.

A novel role of breast cancer-derived hyaluronan on inducement of M2-like tumor-associated macrophages formation

“…Moreover, STAT3 activation was inhibited by suppressing ERK1/2 signal during phenotype transition of macrophages. Our data, together with previous studies indicating that STAT3 may serve as the downstream signal of ERK1/2, 48,49 suggest that ERK1/2-STAT3 pathway is the molecular cue responsible for HA-mediated TAM formation. Based on these results, we conclude that macrophages within breast tumor microenvironment transform to M2 cells through HA-CD44-ERK1/2-STAT3 pathway that may be valuable as a target in suppressing TAM formation.…”

A novel role for C–C motif chemokine receptor 2 during infection with hypervirulent Mycobacterium tuberculosis

“…4e and Supplementary Table 5), including inhibitor of DNA binding 1 ( Id1; expressed by tissue-resident macrophages 28 ) and growth differentiation factor-15 ( Gdf15 ), which has been reported to drive expression of CCR2 in macrophages 29 . Further, significantly higher gene expression in airway AMs was observed for Toll like receptor (TLR)-induced inflammatory responses such as Polo-like kinase 3 ( Plk3 ) 30 and Pleckstrin homology like domain, family A, member 1 ( Phlda1 ) 31 and the cholesterol–trafficking START domain containing 9 ( Stard9 ) genes. Genes significantly higher in airway AMs from infected mice compared to uninfected mice demonstrated significant enrichment for pathways associated with metabolic pathways, antigen processing and phagocytosis (Supplementary Table 6).…”

PHLDA1 Promotes Lung Contusion by Regulating the Toll-Like Receptor 2 Signaling Pathway

“…TLRs are non-catalytic receptors characteristically expressed on innate immune cells such as macrophages and dendritic cells, and play important roles in the immune system though recognition of non-self matter [16]. The TLR2-mediated signaling pathway is mainly involved in inflammatory reactions, such as lung contusion [15].…”

“…The TLR2-mediated signaling pathway is mainly involved in inflammatory reactions, such as lung contusion [15]. Lyu et al showed that TLR2 stimulation could increase PHLDA1 expression via the JAK2-ERK1/2-STAT3 signaling pathway [16], indicating a relationship between TLR2 and PHLDA1. We investigated if PHLDA1 promoted lung contusion by regulating the TLR2 signaling pathway.…”