Asef2 Functions as a Cdc42 Exchange Factor and Is Stimulated by the Release of an Autoinhibitory Module from a Concealed C-Terminal Activation Element

Hamann, Michael J.; Lubking, Casey M.; Luchini, Doris N.; Billadeau, Daniel D.

doi:10.1128/mcb.01608-06

Cited by 49 publications

(73 citation statements)

References 41 publications

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“…Although the ASEF-related GEFs collybistin 6,28 and ASEF2 (ref. 7 ) are specific for CDC42, the specificity of ASEF for Rho GTPases has been controversial. Initial reports indicated that ASEF was a RAC1-specific GEF 8,9,29 , whereas a recent study 18 showed that ASEF was specific for CDC42 and not RAC1.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a different mechanism for ASEF2 autoinhibition has been put forth, in which interactions between the ABR and SH3 domains and regions on the C-terminal side of the PH domain are important for its autoinhibition 7 . However, for both ASEF and ASEF2, we find that removal of the C-terminal region following the PH domain does not influence the exchange potential of these GEFs (see Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

“…However, APC Arm has been reported to interact with the SH3 domain and not the ABR of ASEF2 to stimulate GEF activity 7 . We found that ASEF2 ΔN (containing the ABR) was robustly stimulated by APC Arm to catalyze nucleotide exchange on CDC42, whereas ASEF2 ΔABR4 (no ABR) was not (Fig.…”

Section: Identification Of the Core Apc-binding Motifmentioning

confidence: 99%

“…DH and PH domains in Dbl proteins catalyze the exchange of GDP for GTP in Rho GTPases, allowing them to signal to downstream effectors 5 . ASEF is homologous to the Dbl proteins collybistin (also called PEM2) and SPATA13 (also called ASEF2), both of which have been shown to activate specifically CDC42 and not other Rhofamily GTPases 6,7 .…”

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confidence: 99%

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Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression

Mitin

Betts

Yohe

et al. 2007

Nat Struct Mol Biol

116

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Autoinhibition of the Rho guanine nucleotide exchange factor ASEF is relieved by interaction with the APC tumor suppressor. Here we show that binding of the armadillo repeats of APC to a 'core APC-binding' (CAB) motif within ASEF, or truncation of the SH3 domain of ASEF, relieves autoinhibition, allowing the specific activation of CDC42. Structural determination of autoinhibited ASEF reveals that the SH3 domain forms an extensive interface with the catalytic DH and PH domains to obstruct binding and activation of CDC42, and the CAB motif is positioned adjacent to the SH3 domain to facilitate activation by APC. In colorectal cancer cell lines, full-length, but not truncated, APC activates CDC42 in an ASEF-dependent manner to suppress anchorage-independent growth. We therefore propose a model in which ASEF acts as a tumor suppressor when activated by APC and inactivation of ASEF by mutation or APC truncation promotes tumorigenesis.The adenomatous polyposis coli (APC) protein is a negative regulator of the Wnt signaling pathway and promotes the phosphorylation and degradation of β-catenin 1 . The majority of colorectal cancers (CRCs) harbor C-terminally truncated forms of APC that retain the Nterminal coiled-coil domain and the highly conserved armadillo repeat region (APC Arm ) 2 and are unable to regulate the degradation of β-catenin 3 . Recent studies suggest that APC regulates cytoskeletal dynamics to influence cellular migration, cell division, polarization and adhesion, and it seems increasingly likely that deregulated cytoskeletal dynamics, together with enhancement of transcription by β-catenin, potentiate tumor formation and progression upon APC truncation. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptAPC may regulate cytoskeletal networks by binding to microtubules and to proteins implicated in reorganization of the actin cytoskeleton, such as the Rho effectors mDia and IQGAP1 and the Rho guanine nucleotide exchange factor (RhoGEF) 'APC-stimulated guanine nucleotide exchange factor' (ASEF, also called ARHGEF4) 4 . ASEF is a Dbl-family GEF that contains an Src-homology-3 (SH3) domain followed by the Dbl-homology (DH) and pleckstrinhomology (PH) domains characteristic of Dbl-family GEFs that specifically activate members of the Rho family of GTPases. DH and PH domains in Dbl proteins catalyze the exchange of GDP for GTP in Rho GTPases, allowing them to signal to downstream effectors 5 . ASEF is homologous to the Dbl proteins collybistin (also called PEM2) and SPATA13 (also called ASEF2), both of which have been shown to activate specifically CDC42 and not other Rhofamily GTPases 6,7 .Previous data suggest that ASEF exists in an autoinhibited form and is activated upon binding of APC Arm to the region termed the APC-binding region (ABR) 8 . Binding of APC Arm to the ABR stimulates activation of the Rho GTPase RAC1 by ASEF. Furthermore, truncation of the ABR is sufficient to relieve autoinhibition, rendering ASEF constitutively active. In addition, truncated, but not wild-...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Identification Of the Core Apc-binding Motifmentioning

confidence: 99%

mentioning

confidence: 99%

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Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression

Mitin

Betts

Yohe

et al. 2007

Nat Struct Mol Biol

116

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“…APC has also been shown to interact with various cellular proteins other than ␤-catenin and to regulate cytoskeletal networks (7)(8)(9)(10)(11)(12)(13)(14)(15). For example, APC binds via its armadillo repeat domain to the NH 2 -terminal regions of Asef and Asef2, guanine-nucleotide exchange factors (GEFs) specific for Rac1 and Cdc42 (9,11,(15)(16).…”

Section: From the Laboratory Of Molecular And Genetic Information Inmentioning

confidence: 99%

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

Kawasaki

Jigami

Furukawa

et al. 2010

Journal of Biological Chemistry

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ZRANB2 localizes to supraspliceosomes and influences the alternative splicing of multiple genes in the transcriptome

et al. 2013

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Alternative splicing is a major source of protein diversity in humans. The human splicing factor zinc finger, Ran-binding domain containing protein 2 (ZRANB2) is a splicing protein whose specific endogenous targets are unknown. Its upregulation in grade III ovarian serous papillary carcinoma could suggest a role in some cancers. To determine whether ZRANB2 is part of the supraspliceosome, nuclear supernatants from human embryonic kidney 293 cells were prepared and then fractioned on a glycerol gradient, followed by Western blotting. The same was done after treatment with a tyrosine kinase to induce phosphorylation. This showed for the first time that ZRANB2 is part of the supraspliceosome, and that phosphorylation affects its subcellular location. Studies were then performed to understand the splicing targets of ZRANB2 at the whole-transcriptome level. HeLa cells were transfected with a vector containing ZRANB2 or with a vector-only control. RNA was extracted, converted to cDNA and hybridized to Affymetrix GeneChip(®) Human Exon 1.0 ST Arrays. At the FDR ≤1.3 significance level we found that ZRANB2 influenced the alternative splicing of primary transcripts of CENTB1, WDR78, C10orf18, CABP4, SMARCC2, SPATA13, OR4C6, ZNF263, CAPN10, SALL1, ST18 and ZP2. Several of these have been implicated in tumor development. In conclusion ZRANB2 is part of the supraspliceosome and causes differential splicing of numerous primary transcripts, some of which might have a role in cancer.

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Asef2 Functions as a Cdc42 Exchange Factor and Is Stimulated by the Release of an Autoinhibitory Module from a Concealed C-Terminal Activation Element

Cited by 49 publications

References 41 publications

Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression

Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression

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

ZRANB2 localizes to supraspliceosomes and influences the alternative splicing of multiple genes in the transcriptome

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