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Mitchell, Jonathon,Kim, Su Jin,Seelmann, Alexandra,Veit, Brendan,Shepard, Brooke,Im, Eunok,Rhee, Sang Hoon Elsevier 2018 Biochemical pharmacology Vol.147 No.-
<P><B>Abstract</B></P> <P>Src family kinases (SFKs) are a family of protein tyrosine kinases containing nine members: Src, Lyn, Fgr, Hck, Lck, Fyn, Blk, Yes, and Ylk. Although SFK activation is a major immediate signaling event in LPS/Toll-like receptor 4 (TLR4) signaling, its precise role has remained elusive due to various contradictory results obtained from a certain SFK member-deficient mice or cells. The observed inconsistencies may be due to the compensation or redundancy by other SFKs upon a SFK deficiency. The chemical rescuing approach was suggested to induce temporal and precise SFK activation in living cells, thereby limiting the chance of cellular adaption to a SFK-deficient condition.</P> <P>Using the rescuing approach, we demonstrate that restoring SFK activity not only induces tyrosine phosphorylation of TLR4, but also inhibits LPS-induced NFκB and JNK1/2 activation and consequently suppresses LPS-induced cytokine production. TLR4 normally recruits TIR domain-containing adaptors in response to LPS, however, temporally restored SFK activation disrupts the LPS-induced association of MyD88 and Mal/Tirap with TLR4. Additionally, using kinase-dead SFK-Lyn (Y397/508F) and constitutively active SFK-Lyn (Y508F), we found that the kinase-dead SFK inhibits TLR4 tyrosine phosphorylation with reduced binding affinity to TLR4, while the kinase-active SFK strongly binds to TLR4 and promotes TLR4 tyrosine phosphorylation, suggesting that SFK kinase activity is required for TLR4 tyrosine phosphorylation and TLR4-SFK interaction.</P> <P>Together, our results demonstrate that SFK activation induces TLR4 tyrosine phosphorylation, consequently dissociating MyD88 and Mal/Tirap from TLR4 and inhibiting LPS-induced inflammatory responses, suggesting a negative feedback loop regulated by SFK-induced tyrosine phosphorylation in TLR4.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Cody Howe,Jonathon Mitchell,Su Jin Kim,Eunok Im,Sang Hoon Rhee 한국미생물학회 2019 The journal of microbiology Vol.57 No.11
Although phosphatase and tensin homolog (PTEN) is typically considered a tumor-suppressor gene, it was recently suggested that PTEN regulates TLR5-induced immune and inflammatory responses in intestinal epithelial cells (IECs), suggesting an immunomodulatory function of PTEN in the gut. However, this alternative function of PTEN has not yet been evaluated in an in vivo context of protection against enteropathogenic bacteria. To address this, we utilized IECrestricted Pten knockout (PtenΔIEC/ΔIEC) and littermate Pten+/+ mice. These mice were subjected to the streptomycin-pretreated mouse model of Salmonella infection, and subsequently given an oral gavage of a low inoculum (2 × 104 CFU) of Salmonella enterica serovar Typhimurium (S. Typhimurium). This bacterial infection not only increased the mortality of PtenΔIEC/ΔIEC mice compared to Pten+/+ mice, but also induced deleterious gastrointestinal inflammation in PtenΔIEC/ΔIEC mice manifested by massive histological damage to the intestinal mucosa. S. Typhimurium infection upregulated pro-inflammatory cytokine production in the intestine of PtenΔIEC/ΔIEC mice compared to controls. Furthermore, bacterial loads were greatly increased in the liver, mesenteric lymph node, and spleen of PtenΔIEC/ΔIEC mice compared to controls. Together, these results suggest that IEC-restricted Pten deficiency renders the host greatly susceptible to Salmonella infection and support an immuneregulatory role of PTEN in the gut.
Howe, Cody,Kim, Su Jin,Mitchell, Jonathon,Im, Eunok,Kim, Yong Sung,Kim, You Sun,Rhee, Sang Hoon Elsevier 2018 Biochimica et biophysica acta Vol.1864 No.12
<P><B>Abstract</B></P> <P>Phosphatase and tensin homolog (Pten) antagonizes PI3K-Akt signaling; therefore, Pten impairment causes tumorigenesis. However, the correlation between Pten deficiency and colon cancer has remained elusive due to numerous opposite observations. To study this correlation, we examined whether Pten deficiency in intestinal epithelial cells (IECs) induces tumorigenesis.</P> <P>With mucosal biopsies of human colon cancer and normal colon, Pten mRNA was evaluated by quantitative PCR. Using IEC-specific Pten knockout mice (Pten<SUP>ΔIEC/ΔIEC</SUP>), we examined the mitotic activity of IECs; and Pten<SUP>ΔIEC/ΔIEC</SUP>; Apc<SUP>min/+</SUP> mice were generated by combining Pten<SUP>ΔIEC/ΔIEC</SUP> with Apc<SUP>min/+</SUP> mice. Tumor-associated gene was evaluated by micro-array analysis. Fecal microbiome was analyzed through 16S rRNA gene sequencing.</P> <P>We found that Pten mRNA level was reduced in human colon cancer relative to normal tissues. Augmented chromatids, increased Ki-67 and PCNA expression, and enhanced Akt activation were identified in IECs of Pten<SUP>ΔIEC/ΔIEC</SUP> mice compared to Pten<SUP>+/+</SUP> littermate. Combining Pten<SUP>ΔIEC/ΔIEC</SUP> with Apc<SUP>min/+</SUP> condition caused rapid and aggressive intestinal tumorigenesis. However, Pten<SUP>ΔIEC/ΔIEC</SUP> mice did not develop any tumors. While maintaining the tumor-driving potential, these data indicated that IEC-Pten deficiency alone did not induce tumorigenesis in mice. Furthermore, the expression of tumor-promoting and tumor-suppressing genes was decreased and increased, respectively, in the intestine of Pten<SUP>ΔIEC/ΔIEC</SUP> mice compared to controls. The abundance of <I>Akkermansia muciniphila</I>, capable of inducing chronic intestinal inflammation, was diminished in Pten<SUP>ΔIEC/ΔIEC</SUP> mice compared to controls.</P> <P>These findings suggested that altered tumor-associated gene expression and changed gut microbiota shape a tumor-preventive microenvironment to counteract the tumor-driving potential, leading to the tumor prevention in Pten<SUP>ΔIEC/ΔIEC</SUP> mice.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Pten gene expression is reduced in human colon cancer biopsies. </LI> <LI> However, IEC-specific Pten-KO does not induce tumorigenesis in mice. </LI> <LI> IEC-Pten-KO mice differentially express tumor-associated genes in the gut. </LI> <LI> IEC-Pten-KO mice harbor low level of colitogenic bacteria, <I>Akkermansia muciniphila</I>. </LI> <LI> Altered gut microbiome and gene expression shape a tumor-preventive environment. </LI> </UL> </P>