The Adenomatous Polyposis Coli-associated Guanine Nucleotide Exchange Factor Asef Is Involved in Angiogenesis

Kawasaki, Yuki; Jigami, Takafumi; Furukawa, Shigeto; Sagara, Masaki; Echizen, Kanae; Shibata, Yoko; Sato, Ryo; Akiyama, Tetsu

doi:10.1074/jbc.m109.040691

Cited by 27 publications

(18 citation statements)

References 36 publications

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“…Therefore, dissociation of Stau1 from Asef1 could be regulated by the strength or type of neuronal activity. Various growth factors, such as hepatocyte growth factor, basic fibroblast growth factor, and epidermal growth factor, can induce the formation of Asef1-APC complexes and their localization to membrane ruffles and lamellopodia, which is mediated by PI3K and the PH domain of Asef1 (Kawasaki et al 2010). Additionally, PI3K is essential for Asef2-mediated cell migration (Bristow et al 2009).…”

Section: Discussionmentioning

confidence: 99%

“…) and angiogenesis (Kawasaki et al . ) in various cancer cell types. However, Asef1's role in neurons was not clear.…”

mentioning

confidence: 99%

“…The GEF activity of Asef1 is induced by the binding of APC to its N-terminus (Akiyama and Kawasaki 2006). The role of Asef1 has been widely studied in cellular processes, such as cell migration (Kawasaki et al 2009) and angiogenesis (Kawasaki et al 2010) in various cancer cell types. However, Asef1's role in neurons was not clear.…”

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confidence: 99%

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Adenomatous polyposis coli‐stimulated GEF 1 (Asef1) is a negative regulator of excitatory synaptic function

Lim

Yoo

et al. 2018

Journal of Neurochemistry

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Guanine nucleotide exchange factors (GEFs) play important roles in many cellular processes, including regulation of the structural plasticity of dendritic spines. A GEF protein, adenomatous polyposis coli-stimulated GEF 1 (Asef1, ARHGEF4) is highly expressed in the nervous system. However, the function of Asef1 has not been investigated in neurons. Here, we present evidence showing that Asef1 negatively regulates the synaptic localization of postsynaptic density protein 95 (PSD-95) in the excitatory synapse by inhibiting Staufen-mediated synaptic localization of PSD-95. Accordingly, Asef1 expression impairs synaptic transmission in hippocampal cultured neurons. In addition, neuronal activity facilitates the dissociation of Asef1 from Staufen in a phosphoinositide 3 kinase (PI3K)-dependent manner. Taken together, our data reveal Asef1 functions as a negative regulator of synaptic localization of PSD-95 and synaptic transmission.

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Section: Discussionmentioning

confidence: 99%

“…) and angiogenesis (Kawasaki et al . ) in various cancer cell types. However, Asef1's role in neurons was not clear.…”

mentioning

confidence: 99%

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Adenomatous polyposis coli‐stimulated GEF 1 (Asef1) is a negative regulator of excitatory synaptic function

Lim

Yoo

et al. 2018

Journal of Neurochemistry

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“…Asef is constitutively activated by truncated APC, stimulates the GEF activity of Cdc42, and promotes tumor invasion and angiogenesis [17,[20][21][22][25][26][27]. It has been noted that compounds targeting Asef could be novel anti-tumor reagents [26,27].…”

Section: Discussionmentioning

confidence: 99%

“…The activated Asef catalyzes the exchange of GDP for GTP in Cdc42, decreases cell-cell adhesion, and promotes cell migration [17,[20][21][22]. In colorectal cancers, truncated APC constitutively activates Asef and Cdc42, which upregulate the expression of matrix metalloproteinase 9 (MMP9) via the c-Jun N-terminal kinase (JNK) pathway, thus promotes cancercell migration and angiogenesis [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Structural basis for the recognition of Asef by adenomatous polyposis coli

et al. 2011

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Adenomatous polyposis coli (APC) regulates cell-cell adhesion and cell migration through activating the APCstimulated guanine nucleotide-exchange factor (GEF; Asef), which is usually autoinhibited through the binding between its Src homology 3 (SH3) and Dbl homology (DH) domains. The APC-activated Asef stimulates the small GTPase Cdc42, which leads to decreased cell-cell adherence and enhanced cell migration. In colorectal cancers, truncated APC constitutively activates Asef and promotes cancer cell migration and angiogenesis. Here, we report crystal structures of the human APC/Asef complex. We find that the armadillo repeat domain of APC uses a highly conserved surface groove to recognize the APC-binding region (ABR) of Asef, conformation of which changes dramatically upon binding to APC. Key residues on APC and Asef for the complex formation were mutated and their importance was demonstrated by binding and activity assays. Structural superimposition of the APC/Asef complex with autoinhibited Asef suggests that the binding between APC and Asef might create a steric clash between Asef-DH domain and APC, which possibly leads to a conformational change in Asef that stimulates its GEF activity. Our structures thus elucidate the molecular mechanism of Asef recognition by APC, as well as provide a potential target for pharmaceutical intervention against cancers.

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Mechanisms of RAS/β-catenin interactions

et al. 2013

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Signaling through the WNT/β-catenin and the RAS (rat sarcoma)/MAPK (mitogen-activated protein kinase) pathways plays a key role in the regulation of various physiological cellular processes including proliferation, differentiation, and cell death. Aberrant mutational activation of these signaling pathways is closely linked to the development of cancer in many organs, in humans as well as in laboratory animals. Over the past years, more and more evidence for a close linkage of the two oncogenic signaling cascades has accumulated. Using different experimental approaches, model systems, and experimental conditions, a variety of molecular mechanisms have been identified by which signal transduction through WNT/β-catenin and RAS interact, either in a synergistic or an antagonistic manner. Mechanisms of interaction comprise an upstream crosstalk at the level of pathway-activating ligands and their receptors, interrelations of cytosolic kinases involved in either pathways, as well as interaction in the nucleus related to the joint regulation of target gene transcription. Here, we present a comprehensive review of the current knowledge on the interaction of RAS/MAPK- and WNT/β-catenin-driven signal transduction in mammalian cells.

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The Adenomatous Polyposis Coli-associated Guanine Nucleotide Exchange Factor Asef Is Involved in Angiogenesis

Cited by 27 publications

References 36 publications

Adenomatous polyposis coli‐stimulated GEF 1 (Asef1) is a negative regulator of excitatory synaptic function

Adenomatous polyposis coli‐stimulated GEF 1 (Asef1) is a negative regulator of excitatory synaptic function

Structural basis for the recognition of Asef by adenomatous polyposis coli

Mechanisms of RAS/β-catenin interactions

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