WAVE2 deficiency reveals distinct roles in embryogenesis and Rac-mediated actin-based motility

Yan, Catherine T.

doi:10.1093/emboj/cdg350

Cited by 166 publications

(190 citation statements)

References 44 publications

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“…For example, inactivation of murine WAVE2 is lethal by E12.5 (during mid-gestation) (16); inactivation of N-WASP is lethal at E11.0 (during organogenesis) (33,41); inactivation of Cdc42 is lethal at E3.5 (during implantation) (42); inactivation of Nap1 is lethal at E9.0 (during gastrulation); and inactivation of Rac1 is lethal at E7.5 (during gastrulation) (32,43,44). Abi2 mutants are viable and without morphological defects (27).…”

Section: Discussionmentioning

confidence: 99%

“…WAVE1 and WAVE3 were proposed to have roles analogous to WAVE2 in the complex (8). Although the function of WAVE3 is less defined, the critical role of the other two WAVEs in dorsal ruffle formation was demonstrated (15,16). Mechanistically, it is proposed that native WAVE2 complex is inactive (17)(18)(19) but is activated at the membrane by simultaneous interaction with prenylated Rac-GTP and acidic phospholipids as well as by serine/threonine phosphorylation (20).…”

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confidence: 99%

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Essential role for Abi1 in embryonic survival and WAVE2 complex integrity

Dubielecka

Ladwein

Xiong

et al. 2011

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

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Abl interactor 1 (Abi1) plays a critical function in actin cytoskeleton dynamics through participation in the WAVE2 complex. To gain a better understanding of the specific role of Abi1, we generated a conditional Abi1-KO mouse model and MEFs lacking Abi1 expression. Abi1-KO cells displayed defective regulation of the actin cytoskeleton, and this dysregulation was ascribed to altered activity of the WAVE2 complex. Changes in motility of Abi1-KO cells were manifested by a decreased migration rate and distance but increased directional persistence. Although these phenotypes did not correlate with peripheral ruffling, which was unaffected, Abi1-KO cells exhibited decreased dorsal ruffling. Western blotting analysis of Abi1-KO cell lysates indicated reduced levels of the WAVE complex components WAVE1 and WAVE2, Nap1, and Sra-1/PIR121. Although relative Abi2 levels were more than doubled in Abi1-KO cells, the absolute Abi2 expression in these cells amounted only to a fifth of Abi1 levels in the control cell line. This finding suggests that the presence of Abi1 is critical for the integrity and stability of WAVE complex and that Abi2 levels are not sufficiently increased to compensate fully for the loss of Abi1 in KO cells and to restore the integrity and function of the WAVE complex. The essential function of Abi1 in WAVE complexes and their regulation might explain the observed embryonic lethality of Abi1-deficient embryos, which survived until approximately embryonic day 11.5 and displayed malformations in the developing heart and brain. Cells lacking Abi1 and the conditional Abi1-KO mouse will serve as critical models for defining Abi1 function.cell motility | lamellipodium | Rac | Arp2/3-complex | Hssh3bp1

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Essential role for Abi1 in embryonic survival and WAVE2 complex integrity

Dubielecka

Ladwein

Xiong

et al. 2011

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

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“…Another group reported that lysates from WAVE2 knockout MEFs, which express other isoforms of WAVEs, do not show Rac-induced in vitro actin polymerization (Yan et al, 2003). In these MEFs, WAVE2 and WAVE1 play roles in cell migration in ECM.…”

Section: Discussionmentioning

confidence: 99%

“…Rac1 activates actin polymerization through WASP family verprolin-homologous proteins (WAVE) and Arp2/3 complex leading to formation of membrane ruffles that push the cell membrane forward (Takenawa and Miki, 2001;Suetsugu et al, 2002a). Although WAVEs have been shown to be involved in morphogenesis and motility of cells and in embryonic development of mice (Soderling et al, 2003;Suetsugu et al, 2003;Yamazaki et al, 2003;Yan et al, 2003), their roles in cancer invasion and metastasis remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Rac-WAVE2 signaling is involved in the invasive and metastatic phenotypes of murine melanoma cells

et al. 2004

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WAVEs (WASP-family verprolin-homologous proteins) regulate the actin cytoskeleton through activation of Arp2/3 complex. As cell motility is regulated by actin cytoskeleton rearrangement and is required for tumor invasion and metastasis, blocking actin polymerization may be an effective strategy to prevent tumor dissemination. We show that WAVEs, especially WAVE2, are essential for invasion and metastasis of melanoma cells. Malignant B16F10 mouse melanoma cells expressed more WAVE1 and WAVE2 proteins and showed higher Rac activity than B16 parental cells, which are neither invasive nor metastatic. The effect of WAVE2 silencing by RNA interference (RNAi) on the highly invasive nature of B16F10 cells was more dramatic than that of WAVE1 RNAi. Membrane ruffling, cell motility, invasion into the extracellular matrix, and pulmonary metastasis of B16F10 cells were suppressed by WAVE2 RNAi. WAVE2 RNAi also had a profound effect on invasion induced by a constitutively active form of Rac (RacCA). In addition, ectopic expression of both RacCA and WAVE2 in B16 cells resulted in further increase in the invasiveness than that observed in B16 cells expressing only RacCA. Thus, WAVE2 acts as the primary effector downstream of Rac to achieve invasion and metastasis, suggesting that suppression of WAVE2 activity holds a promise for preventing cancer invasion and metastasis.

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“…WASP proteins are dispensable for the formation of lamellipodia (2,3), whereas Wave proteins have emerged as a critical regulator of this structure. In fact, Wave proteins are localized at the tip of the protruding lamellipodium and delocalized whenever this structure retracts (4); genetic inactivation of the ubiquitously expressed Wave-2 gene causes defects in the formation of lamellipodia (5,6). These results highlight the importance of the Wave-Arp2͞3 pathway in the formation of lamellipodia in migrating cells.…”

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confidence: 99%

Purification and architecture of the ubiquitous Wave complex

Gautreau

et al. 2004

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

212

286

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The Wave proteins are major activators of the Arp2͞3 complex. The ubiquitous Wave-2 is required for actin polymerization at the leading edge of migrating cells. Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex. These proteins are only present in the complexed form, with the exception of Hspc, which displays a free pool. We reconstitute the Wave-2 complex by cotranslating in vitro the five subunits and use this system together with specific immunoprecipitations to study the molecular architecture of the complex. The complex is organized around a core of Nap and Abi. Sra is a peripheral subunit recruited on the Nap side, whereas the Wave and Hspc subunits are recruited on the Abi side of the core.

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WAVE2 deficiency reveals distinct roles in embryogenesis and Rac-mediated actin-based motility

Cited by 166 publications

References 44 publications

Essential role for Abi1 in embryonic survival and WAVE2 complex integrity

Essential role for Abi1 in embryonic survival and WAVE2 complex integrity

Rac-WAVE2 signaling is involved in the invasive and metastatic phenotypes of murine melanoma cells

Purification and architecture of the ubiquitous Wave complex

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