Polyamine-dependent activation of Rac1 is stimulated by focal adhesion-mediated Tiam1 activation

Elias, Bertha C.; Bhattacharya, Sujoy; Ray, Ramesh R.; Johnson, Leonard R.

doi:10.4161/cam.4.3.12043

Cited by 18 publications

(23 citation statements)

References 37 publications

(36 reference statements)

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“…The mechanism of c-Src-mediated tight junction disruption involves Tyr-phosphorylation of tight junction and adherens junction proteins [16, 37]. Tyr-phosphorylation of tight junction and adherens junction proteins are known to weaken the integrity of AJC [38, 39]. Therefore, we investigated the potential role of c-Src activation in DSS-induced tight junction disruption.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the mechanism involving JNK-mediated Tyr-phosphorylation of tight junction proteins, likely via c-Src activation, also exists in the mouse colonic epithelium in vivo . Phosphorylation of occludin on Y398 and Y402 was previously shown to attenuate its interaction with ZO-1 and weaken tight junction integrity [38, 39]. It is likely that DSS induces Tyr-phosphorylation of occludin on Y398 and Y402 residues.…”

Section: Discussionmentioning

confidence: 99%

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Calcium/Ask1/MKK7/JNK2/c-Src signalling cascade mediates disruption of intestinal epithelial tight junctions by dextran sulfate sodium

Samak

Chaudhry

Gangwar

et al. 2015

Biochemical Journal

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Disruption of intestinal epithelial tight junctions is an important event in the pathogenesis of ulcerative colitis. Dextran sodium sulfate (DSS) induces colitis in mice with the symptoms similar to ulcerative colitis. However, the mechanism of DSS-induced colitis is unknown. We investigated the mechanism of DSS-induced disruption of intestinal epithelial tight junctions and barrier dysfunction in Caco-2 cell monolayers in vitro and mouse colon in vivo. DSS treatment resulted in disruption of tight junctions, adherens junctions and actin cytoskeleton leading to barrier dysfunction in Caco-2 cell monolayers. DSS induced a rapid activation of c-jun N-terminal kinase (JNK), and the inhibition or knockdown of JNK2 attenuated DSS-induced tight junction disruption and barrier dysfunction. In mice, DSS administration for 4 days caused redistribution of tight junction and adherens junction proteins from the epithelial junctions, which was blocked by JNK inhibitor. In Caco-2 cell monolayers, DSS increased intracellular Ca2+ concentration, and depletion of intracellular Ca2+ by BAPTA or thapsigargin attenuated DSS-induced JNK activation, tight junction disruption and barrier dysfunction. Knockdown of Ask1 or MKK7 blocked DSS-induced tight junction disruption and barrier dysfunction. DSS activated c-Src by a Ca2+ and JNK-dependent mechanism. Inhibition of Src kinase activity or knockdown of c-Src blocked DSS-induced tight junction disruption and barrier dysfunction. DSS increased Tyr-phosphorylation of occludin, ZO-1, E-cadherin and β-catenin. SP600125 abrogated DSS-induced Tyr-phosphorylation of junctional proteins. Recombinant JNK2 induced threonine phosphorylation and auto phosphorylation of c-Src. This study demonstrates that Ca2+-Ask1-MKK7-JNK2-cSrc signaling cascade mediates DSS-induced tight junction disruption and barrier dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Calcium/Ask1/MKK7/JNK2/c-Src signalling cascade mediates disruption of intestinal epithelial tight junctions by dextran sulfate sodium

Samak

Chaudhry

Gangwar

et al. 2015

Biochemical Journal

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“…We and others have shown that FAK may contribute to Rac activation in hematopoietic cells as well as in other heterologous cell systems (Chang et al, 2006; Elias et al, 2010; Vemula et al, 2010) and that FLT3ITD can activate Rac1 and regulate the production of reactive oxygen species (ROS) via its association with Stat5 (Sallmyr et al, 2008). Furthermore, active Rac1 can also induce the activation and nuclear translocation of Stat3 (Simon et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis

et al. 2014

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SUMMARY Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN) and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK), whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.

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“…Rac1 is held inactive by GDI-1, thus dissociation of GDI-1 is required for the GTP exchange by Rac- guanine exchange factor (GEF)s, such as Tiam-1 and Vav2 (Crespo et al, 1997; Mertens et al, 2003). FAK regulates Rac-GEF Tiam1 (Elias et al, 2010). Activated FAK associates with GIT1 and GIT2 following focal adhesion redistribution (Shikata et al, 2003a).…”

Section: S1pr and Endothelial Barrier Functionmentioning

confidence: 99%

Heterotrimeric G proteins, focal adhesion kinase, and endothelial barrier function

Thennes¹,

Mehta²

2012

Microvascular Research

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Ligands by binding to G protein coupled receptors (GPCRs) stimulate dissociation of heterotrimeric G proteins into Gα and Gβγ subunits. Released Gα and Gβγ subunits induce discrete signaling cues that differentially regulate focal adhesion kinase (FAK) activity and endothelial barrier function. Activation of G proteins downstream of receptors such as protease activated receptor 1 (PAR1) and histamine receptors rapidly increases endothelial permeability which reverses naturally within the following one to two hours. However, activation of G proteins coupled to the sphingosine-1-phosphate receptor 1 (S1P1) signal cues that enhance basal barrier endothelial function and restore endothelial barrier function following the increase in endothelial permeability by edemagenic agents. Intriguingly, both PAR1 and S1P1 activation stimulates FAK activity, which associates with alteration in endothelial barrier function by these agonists. In this review, we focus on the role of the G protein subunits downstream of PAR1 and S1P1 in regulating FAK activity and endothelial barrier function.

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Polyamine-dependent activation of Rac1 is stimulated by focal adhesion-mediated Tiam1 activation

Cited by 18 publications

References 37 publications

Calcium/Ask1/MKK7/JNK2/c-Src signalling cascade mediates disruption of intestinal epithelial tight junctions by dextran sulfate sodium

Calcium/Ask1/MKK7/JNK2/c-Src signalling cascade mediates disruption of intestinal epithelial tight junctions by dextran sulfate sodium

Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis

Heterotrimeric G proteins, focal adhesion kinase, and endothelial barrier function

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