Characterization of STEF, a Guanine Nucleotide Exchange Factor for Rac1, Required for Neurite Growth

Matsuo, Naoki; Hoshino, Mikio; Yoshizawa, Masato; Nabeshima, Yo Ichi

doi:10.1074/jbc.m106186200

Cited by 84 publications

(94 citation statements)

References 42 publications

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“…Control siRNA had no effect on these parameters. In so doing, they complement and extend the results of recent studies that demonstrated an important role for STEF and Rac1 in mediating neurite outgrowth from neuroblastoma cells (21). Taken together with studies on Cos-7 cells, the observations in neuronal cells offer compelling evidence that BDNF induces changes in cell shape through a signaling pathway that depends critically on direct TrkB-mediated Tyr-829 phosphorylation of Tiam1 with resulting activation of Rac1.…”

Section: Resultssupporting

confidence: 70%

“…Overexpression of Tiam1 promotes the formation of lamellipodial structures in fibroblasts and neurites in neuroblastoma cells (14). STEF͞Tiam2, another Rac1-GEF, is highly homologous with Tiam1 and also increases neurite outgrowth (21). Because endogenous Tiam1 was detected at high levels in Cos-7 cells, we set out to study whether Tiam1 mediated BDNF-induced Rac1 activation in these cells.…”

Section: Resultsmentioning

confidence: 99%

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TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology

Miyamoto

Yamauchi

Tanoue

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

135

132

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Small GTPases of the Rho family play key roles in the formation of neuronal axons and dendrites by transducing signals from guidance cues, such as neurotrophins, to the actin cytoskeleton. However, there is little insight into the mechanism by which neurotrophins regulate Rho GTPases. Here, we show the crucial role of the ubiquitous Rac1-specific guanine nucleotide exchange factor, Tiam1 (T lymphoma invasion and metastasis 1), in transducing a neurotrophin-mediated change in cell shape. We demonstrate that BDNF, acting through TrkB, directly binds and specifically activates Tiam1 by phosphorylating Tyr-829, leading to Rac1 activation and lamellipodia formation in Cos-7 cells and increased neurite outgrowth from cortical neurons. A point mutation in Tiam1, Tyr-829 to Phe-829, blocked these BDNF-induced changes in cellular morphology. The findings are evidence of a previously uncharacterized mechanism for the activation of Tiam1 and of a role for this effector in neurotrophin-mediated signal transduction leading to changes in cellular morphology.actin ͉ cortical neuron ͉ neurotrophin ͉ Rho guanine nucleotide exchange factors ͉ Rho GTPases

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Section: Resultssupporting

confidence: 70%

Section: Resultsmentioning

confidence: 99%

TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology

Miyamoto

Yamauchi

Tanoue

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

135

132

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“…Activation of Rac1 GTPase can induce EMT, and regulate the expression of MMPs (Mack et al, 2011). It is reported that TIAM2 is required for the activation of Rac1 GTPase in neuronal and skin papilloma cells (Matsuo et al, 2002;Rooney et al, 2010). Here, we found that TIAM2 could induce the activation of Rac1 in NSCLC cells, further confirming the role of TIAM2 in the regulation of Rac1 activation.…”

Section: Discussionsupporting

confidence: 74%

“…The involvement of TIAM1 in the invasion and metastasis has been well studied in many tumors (Minard et al, 2004). As the homology of TIAM1, TIAM2 has been shown to regulate the reorganization of actin cytoskeletal in neuronal cells (Matsuo et al, 2002;Goto et al, 2011). Recent studies have found that TIAM2 promotes proliferation and invasion in liver cancer cells (Chen et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

TIAM2 Enhances Non-small Cell Lung Cancer Cell Invasion and Motility

Zhao

Han²,

Liu³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: TIAM2, a Rac guanine nucleotide exchange factor, is closely associated with cell adherence and migration. Here, we aimed to investigate the role of TIAM2 in non-small cell lung cancer (NSCLC) cells. Materials and Methods: A small interference RNA (siRNA) was introduced to silence the expression of TIAM2. Invasion and motility assays were then performed to assess the invasion and motility potential of NSCLC cells. GST-pull down assays were used to detect activation of Rac1. Results: TIAM2 was highly expressed in NSCLC cells. Knockdown of TIAM2 inhibited the invasion and motility, and suppressed activation of Rac1. Further experiments demonstrated that knockdown of TIAM2 could up-regulate the expression of E-cadherin, and downregulate the expression of MMP-3, Twist and Snail. Conclusions: Our data suggest that TIAM2 can promote invasion and motility of NSCLC cells. Activation of Rac1 and regulation of some EMT/invasion-related genes may be involved in the underlying processes.

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“…Although A-class ephrins are not highly expressed in the developing mouse cortex (Yun et al, 2003), it is important to examine the expression of Tiam1 and Ephexin, two exchange factors having opposing effects on the neurites motility, in the cortical region. Furthermore, we also have to consider a homologous protein of Tiam1, STEF, another GEF for Rac1, because STEF is also expressed in the cerebral cortex of developing mice (Matsuo et al, 2002;Kawauchi et al, 2003). We detected the association of the PHnTSS domain Because the PHnTSS region of Tiam1 is highly homologous to the PHnTSS domain of STEF, these Tiam1 fragments may also work as dominant-negative mutants for STEF.…”

Section: Discussionmentioning

confidence: 99%

Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2

Tanaka

Ohashi

Nakamura

et al. 2004

EMBO J

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Bidirectional signals mediated by Eph receptor tyrosine kinases and their membrane-bound ligands, ephrins, play pivotal roles in the formation of neural networks by induction of both collapse and elongation of neurites. However, the downstream molecular modules to deliver these cues are largely unknown. We report here that the interaction of a Rac1-specific guanine nucleotide-exchanging factor, Tiam1, with ephrin-B1 and EphA2 mediates neurite outgrowth. In cells coexpressing Tiam1 and ephrin-B1, Rac1 is activated by the extracellular stimulation of clustered soluble EphB2 receptors. Similarly, soluble ephrin-A1 activates Rac1 in cells coexpressing Tiam1 and EphA2. Cortical neurons from the E14 mouse embryos and neuroblastoma cells significantly extend neurites when placed on surfaces coated with the extracellular domain of EphB2 or ephrin-A1, which were abolished by the forced expression of the dominant-negative mutant of ephrin-B1 or EphA2. Furthermore, the introduction of a dominant-negative form of Tiam1 also inhibits neurite outgrowth induced by the ephrin-B1 and EphA2 signals. These results indicate that Tiam1 is required for neurite outgrowth induced by both ephrin-B1-mediated reverse signaling and EphA2-mediated forward signaling.

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Characterization of STEF, a Guanine Nucleotide Exchange Factor for Rac1, Required for Neurite Growth

Cited by 84 publications

References 42 publications

TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology

TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology

TIAM2 Enhances Non-small Cell Lung Cancer Cell Invasion and Motility

Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2

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