IndraLab
Statements
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"The signaling mechanism involved recruitment of sphingosine 1-phosphate receptor-1 (S1P-R1) to the caveolin enriched microdomains (CEMs, also known as lipid rafts or caveoli) and activation of serine/threonine kinases mammalian target of rapamycin (mTOR) and phosphoinositide 3-kinase (PI3K) and Rac specific nucleotide exchange factors Tiam1 and Vav2, which stimulated Rac1 GTPase signaling to cytoskeleton and cell junctions."
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"The reliability of this streamlined approach is demonstrated by the creation of an optogenetic Cdc42 GTPase and Rac1-activating Tiam1 GEF protein, which together with our other recently reported technologies, complete a toolbox for spatiotemporally precise induction of Rho-family GTPase signaling at the GEF or GTPase level, for driving filopodial protrusions, lamellipodial protrusions, and cell contractility respectively mediated by Cdc42, Rac1, and RhoA."
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"The Par complex (Par3, Par6, and PKCzeta) controls cell polarity in part by recruiting the Rac specific guanine nucleotide exchange factor T-lymphoma invasion and metastasis 1 (Tiam1) to specialized cellular sites, where Tiam1 promotes local Rac1 activation and cytoskeletal remodeling."
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"XREF_BIBR Given the importance of the P-Rex1 scaffolding function in stimulating P-Rex1-specific Rac1 interactions, together with the previously reported scaffolding role of Tiam1, it is likely that the observed Tiam1 mediated modulation of the Rac1 interactome is also a consequence of Tiam1 serving as a scaffolding protein."
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"We also showed that prior incubation of INS-1 832/13 cells with GGTI-2147, an inhibitor of geranylgeranylation of Rac1 or NSC23766, a known inhibitor of Rac1 mediated by Tiam1, a guanine nucleotide exchange factor for Rac1 markedly attenuated cytomix induced ROS generation [XREF_BIBR]."
eidos
"DHH promotes filamentous alpha-SMA organization through TIAM1 mediated RAC1 activation Our data demonstrate a critical role for DHH signaling through the primary cilium in the regulation of collagen gel compaction ( Figures 3 and 4 ) and alpha-SMA organization ( Figure 5 , Supplemental Figure 10 ) ."
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"However, and consistent with recent studies, we find that the formation of the signaling complex Tiam1 and Rac1 is not abrogated by inhibition of PI3K using Ly294002, indicating that Tiam1 mediates Rac1 activation by a PI3K independent mechanism XREF_BIBR, XREF_BIBR (XREF_SUPPLEMENTARY)."
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"At the membrane, Tiam1 activates Rac1 and is implicated in cell migration [XREF_BIBR], and whether it is also involved in FA dynamics by virtue of its association with the Syndecan-4 and PAR-3 signaling complex or by binding to PIP 3 at the plasma membrane is yet to be investigated."
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"Note that the 14-3-3ζ-Tiam-1-Rac1 and kindlin-talin complexes can occur on the same β-tail, which enables both changes in integrin avidity and affinity.14-3-3ζ in turn bound to the Tiam1 adaptor protein, which further activated the small G protein Rac-1, which regulates the organization of the actin cytoskeleton [65] ."
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"Moreover, the FRET analysis of Rac1 in U251 cells showed that the region of higher Rac1 activation sometimes, but not always, overlapped with large adhesions, suggesting that Tiam1 at large adhesion activates Rac1 to control adhesion dynamics for cell migration (see following paragraph)."
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"With this in mind, and as a logical extension to our ongoing studies, which provided a compelling evidence for key regulatory roles for Rac1 in GSIS, we undertook the current investigation to determine potential role of Tiam1 mediated Rac1 signaling steps in GSIS in INS 832/13 cells [referred to as beta-cells throughout the manuscript]."
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"Consistent with previously described Tiam1 driven formation of Rac1 dependent cell-cell contacts XREF_BIBR, XREF_BIBR, we observe loss of refractile morphology of Tiam1 expressing fibroblasts under brightfield microscopy at high cell densities which hints at altered cell to cell adhesion (XREF_FIG)."
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"The reliability of this streamlined approach is demonstrated by the creation of an optogenetic Cdc42 GTPase and Rac1-activating Tiam1 GEF protein, which together with our other recently reported technologies, completes a toolbox for spatiotemporally precise induction of Rho-family GTPase signaling at the GEF or GTPase level, for driving filopodial protrusions, lamellipodial protrusions, and cell contractility, respectively mediated by Cdc42, Rac1, and RhoA."
reach
"In conclusion, the ability of R-Ras-GTP to convert RIN2 from a GEF to an adaptor that preferentially binds Rab5-GTP allows the triggering of the endocytosis of ECM-bound and active beta1 integrins and the ensuing funneling of R-Ras-GTP toward early endosomes to elicit the pro adhesive and TIAM1 mediated activation of Rac1."
sparser
"The use of NSC23766 that blocks Rac1 activation by Tiam1, resulted in enhanced LPS- or thrombin-induced endothelial permeability, decreased formation of a stable cortical actin ring at the cell periphery that has been directly correlated with destabilized adherens junctions ( xref ; xref )."
sparser
"Cgnl1 was shown to be an inhibitor of RhoA activity, but was also involved in the activation of Rac1 by the GEF Tiam1 in epithelial cells. xref , xref Like cingulin, Cgnl1 is co-localized with actin filament bundles, implying that it could be a cross-road modulator that links intercellular junction assembly to actin cytoskeleton-regulated morphogenesis, both key processes in angiogenesis."
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"HA (mixed sizes) also promotes the interaction between CD44 and several Rac1 specific guanine nucleotide exchange factors [e.g., Tiam1 and Vav2], thereby up-regulating Rac1 (another member of the Rho subclass of the Ras superfamily), leading to altered cytoskeleton mediated cell functions."
sparser
"Activation of Rac1 by Tiam1 downregulates RhoA in NIH3T3 fibroblasts and induces strengthening of cadherin-based cell–cell adhesion, with transformation of cells to an epithelial-like morphology with suppressed cell migration capabilities. xref Inversely, activation of RhoA induces migratory and fibroblastic phenotype in NIH3T3 fibroblasts."
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"Although our findings provide evidence showing that Tiam1 cooperates with Ras to mediate NGF induced Rac1 activation, the residual activity of Rac1 observed in cells treated with Tiam1 RNAi in the presence of NGF, suggests the existence of alternative Tiam1 independent mechanisms through which NGF can activate Rac1."
sparser
"We propose that Tiam1 activates Rac1 by catalyzing GDP to GTP exchange, and thereby mediates the stimulatory effects of Rac1 on the Wnt-induced transcription factor complex, resulting in the enhanced transcription of a subset of Wnt target genes, including genes that promote unrestricted cell proliferation such as c-Myc and Cyclin D1 ."
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"From the data obtained in this study we conclude that FAK and Src are rapidly activated upon fibronectin mediated signaling leading to Tiam1 mediated Rac1 activation and that intracellular polyamines influence the signaling strength by modulating interaction of Src with Tiam1 using focal adhesion kinase as a scaffolding site."
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"First, it is likely that Tiam1, by itself, or Tiam1 activated Rac1 might control activities of putative transcriptional factors that might play negative modulatory roles in GSIS; regulation of cellular function by such factors [e.g., STAT and c-myc] has been described in other cell types [XREF_BIBR, XREF_BIBR]."
sparser
"At the membrane, Tiam1 activates Rac1 and is implicated in cell migration [ xref ], and whether it is also involved in FA dynamics by virtue of its association with the Syndecan-4/PAR-3 signaling complex or by binding to PIP 3 at the plasma membrane (Fig. xref c) is yet to be investigated."
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"Apparently, various responses by Tiam1 catalyzed Rac1 signaling may be controlled by selective upstream activators (e.g., availability of certain cytoskeletal proteins [e.g., ankyrin], cell adhesion receptors [e.g., CD44, integrin or E-cadherin], growth activators [e.g., serum, S1P, or LPA] or extracellular matrix components [hyaluronic acid, collagen, or fibronectin, etc.])."
sparser
"i) Defects in the activation of Rac1 in endomembranes: It has been demonstrated that Rac1 is activated in endosomes by its GEF Tiam1, following which it is recycled to the leading edge of migratory cells. xref Since Ocrl1 is involved in endosomal trafficking, xref , xref it is possible that subsequent to Rac1 binding, the Lowe syndrome protein facilitates the activation of the RhoGTPase and perhaps its re-routing to the leading edge."
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"XREF_BIBR Interestingly, Tiam1 mediated Rac1 activation has been linked to increased transcriptional and post-transcriptional upregulation of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) and TIMP-2, respectively, while not affecting the secreted levels or activity of Matrix Metalloproteinase-9 (MMP-9) or MMP-2."
sparser
"To address these limitations we recently performed a study directly comparing the ability of 2 distinct Rac-specific GEFs to regulate Rac1 downstream signaling. xref Focusing on Tiam1 and P-Rex1, which have been associated with contrasting migratory phenotypes, xref we first demonstrated that activation of Rac1 by Tiam1 or P-Rex1, irrespective of cell type or upstream signaling, promotes Rac1 anti- vs. pro-migratory effects, respectively. xref Next, to rigorously evaluate the contribution of GEFs in regulating Rac1 signaling through modulating effector binding, we performed a quantitative proteomic analysis of the Rac1 interactome upon activation by either GEF."
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"XREF_BIBR Focusing on Tiam1 and P-Rex1, which have been associated with contrasting migratory phenotypes, XREF_BIBR we first demonstrated that activation of Rac1 by Tiam1 or P-Rex1, irrespective of cell type or upstream signaling, promotes Rac1 anti- vs. pro migratory effects, respectively."
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"Most importantly, we have found that the binding of ankyrin (e.g., erythrocyte ankyrin [ANK1], XREF_FIG A, or ANK3 's ARD, XREF_FIG B) to Tiam1 significantly increases the GDP/GTP exchange activity of Rac1 GTPase as compared with untreated Tiam1 mediated Rac1 activation (XREF_FIG C)."
eidos
"At the membrane , Tiam1 activates Rac1 and is implicated in cell migration [ 71 ] , and whether it is also involved in FA dynamics by virtue of its association with the Syndecan-4 / PAR-3 signaling complex or by binding to PIP3 at the plasma membrane ( Fig. 3c ) is yet to be investigated ."