Interaction with IQGAP1 Links APC to Rac1, Cdc42, and Actin Filaments during Cell Polarization and Migration

Watanabe, Takashi; Wang, Shujie; Noritake, Jun; Sato, Kazumasa; Fukata, Masaki; Takefuji, Mikito; Nakagawa, Masato; Izumi, Nanae; Akiyama, Tetsu; Kaibuchi, Kozo

doi:10.1016/j.devcel.2004.10.017

Cited by 427 publications

(472 citation statements)

References 40 publications

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“…It has been suggested that Scribble might act as a scaffold protein to regulate the localization of membrane associated signalling components and in this way it could mediate the recruitment and localized activation of proteins like Cdc42. It is also possible that Scribble may act downstream of Cdc42 to regulate Golgi/MTOC reorientation through Par6, GSK3b and adenomatous polyposis coli (APC), the latter of which forms ternary complexes with small GTPases at the leading edge (Etienne-Manneville and Hall, 2003;Watanabe et al, 2004). In the astrocyte migration model, Cdc42 activation leads to recruitment of Par6/aPKCz to the leading edge which in turn activates aPKCz and results in phosphorylation of GSK3b Hall, 2001, 2003).…”

Section: Regulation Of Directional Migration By Mammalian Scribblementioning

confidence: 99%

The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge

Dow

Kauffman

Caddy³

et al. 2006

Oncogene

162

143

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Altered expression of human Scribble is associated with invasive epithelial cancers, however, its role in tumour development remains unclear. Mutations in Drosophila Scribble result in loss of polarity, overproliferation and 3D-tumourous overgrowth of epithelial cells. Using complementation studies in Drosophila we recently demonstrated that expression of human Scribble can also regulate polarity and restrict tissue overgrowth. Here, we have undertaken a detailed study of human Scribble function in the polarized mammary cell line, MCF10A. We show that although Scribble does not seem to be required for apical-basal polarity or proliferation control in MCF10A cells, Scribble is essential for the control of polarity associated with directed epithelial cell migration. Scribble-depleted MCF10A cells show defective in vitro wound closure and chemotactic movement. The cells at the wound edge fail to polarize, show reduced lamellipodia formation and impaired recruitment of Cdc42 and Rac1 to the leading edge. Furthermore, we show that this function is relevant in vivo as Scribble mutant mice show defective epidermal wound healing. This data identifies an essential role for mammalian Scribble in the regulation of the polarity specifically involved in directed epithelial migration.

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Section: Regulation Of Directional Migration By Mammalian Scribblementioning

confidence: 99%

The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge

Dow

Kauffman

Caddy³

et al. 2006

Oncogene

162

143

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“…Directional cell migration of Vero cells was stimulated in a monolayer by using an in vitro scratch wound assay 50 . Vero cells were transfected with the indicated siRNAs, and seeded on collagen or poly-D-lysine-precoated 35-mm glass dishes after 24 h of transfection.…”

Section: Plasmidsmentioning

confidence: 99%

The Dishevelled-associating protein Daple controls the non-canonical Wnt/Rac pathway and cell motility

et al. 2012

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Dishevelled is the common mediator of canonical and non-canonical Wnt signalling pathways, which are important for embryonic development, tissue maintenance and cancer progression. In the non-canonical Wnt signalling pathway, the Rho family of small GTPases acting downstream of Dishevelled has essential roles in cell migration. The mechanisms by which the non-canonical Wnt signalling pathway regulates Rac activation remain unknown. Here we show that Daple (Dishevelled-associating protein with a high frequency of leucine residues) regulates Wnt5a-mediated activation of Rac and formation of lamellipodia through interaction with Dishevelled. Daple increases the association of Dishevelled with an isoform of atypical protein kinase C, consequently promoting Rac activation. Accordingly, Daple deficiency impairs migration of fibroblasts and epithelial cells during wound healing in vivo. These findings indicate that Daple interacts with Dishevelled to direct the Dishevelled/protein kinase λ protein complex to activate Rac, which in turn mediates the non-canonical Wnt signalling pathway required for cell migration.

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“…2 online and ref. 25 ). Furthermore, consistent with our in vitro data, concomitant colocalization and ruffle formation were lost when APC Arm was coexpressed with a version of ASEF lacking the ABR (mCherry-ASEF ΔABR4).…”

Section: Full-length But Not Truncated Apc Activates Asefmentioning

confidence: 99%

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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Interaction with IQGAP1 Links APC to Rac1, Cdc42, and Actin Filaments during Cell Polarization and Migration

Cited by 427 publications

References 40 publications

The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge

The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge

The Dishevelled-associating protein Daple controls the non-canonical Wnt/Rac pathway and cell motility

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

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