WAVE3 promotes cell motility and invasion through the regulation of MMP-1, MMP-3, and MMP-9 expression

Sossey‐Alaoui, Khalid; Ranalli, Tamara A.; Li, Xiurong; Bakin, Andrei V.; Cowell, John K.

doi:10.1016/j.yexcr.2005.04.011

Cited by 99 publications

(154 citation statements)

References 53 publications

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“…We determined that Abi1 is not required for mediating phosphorylation of WAVE3 by Abl, contrary to WAVE2, although Abi1 could be found in the same immunocomplex as WAVE3. We finally show that loss of WAVE3 phosphorylation results in inhibition of lamellipodia formation and cell migra-tion, supporting our previous findings that WAVE3 plays a crucial role in these events (3,31).…”

supporting

confidence: 89%

“…More studies are warranted to investigate the specific role of each tyrosine, or the combination of two or more tyrosine residues, in the activity of WAVE3. We have also shown that increased levels of the WAVE3 protein are associated with more aggressive and metastatic stages of human breast cancer (31,36). Another aspect worth investigating is whether increased levels of WAVE3 phosphorylation in breast cancer are also associated with the more aggressive phenotype in these types of tumors.…”

Section: Discussionmentioning

confidence: 78%

“…We have shown that WAVE3 expression is required for lamellipodia formation, cell migration, and invasion, in vitro (3,31). Next, we determined the effect of WAVE3 phosphorylation on the migration of COS7 cells in vitro.…”

Section: Wave3 Phosphorylation By Abl Enhances Cell Migration In Vitro-mentioning

confidence: 98%

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c-Abl-mediated Phosphorylation of WAVE3 Is Required for Lamellipodia Formation and Cell Migration

Sossey‐Alaoui

Cowell

2007

Journal of Biological Chemistry

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121

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The activity of the Wiskott-Aldrich syndrome-related WAVE3 protein is critical for the regulation of the Arp2/3-dependent cytoskeleton organization downstream of Rac-GTPase. The Ableson (Abl) non-receptor tyrosine kinase is also involved in the remolding of actin cytoskeleton in response to extracellular stimuli. Here we show that platelet-derived growth factor stimulation of cultured cells results in WAVE3-Abl interaction and localization to the cell periphery. WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3. We have also shown that Abl targets and phosphorylates four tyrosine residues in WAVE3 and that the Abl-dependent phosphorylation of WAVE3 is critical for the stimulation of lamellipodia formation and cell migration. Our results show that the activation of WAVE3 to promote actin remodeling is enhanced by the c-Ablmediated tyrosine phosphorylation of WAVE3.The actin cytoskeleton plays an important role in cell shape and cell motility (1). Members of the Wiskott-Aldrich syndrome protein (WASP) 2 family that include WASP, neuronal-WASP (N-WASP) and WAVE1, -2, and -3 play crucial roles in actin polymerization through the activation of the actin-related protein (Arp) 2/3 complex (2-4). All five members of the WASP family of proteins contain a conserved C terminus verprolin (V), cofilin (C), and acidic (A) region (VCA domain), which binds to the Arp2/3 complex and stimulates its actin polymerization activity (5). The regulation of the activity of both WASP and N-WASP is thought to be achieved by their inclusion in inactive conformations through intramolecular interaction between the GTPase-binding domain and the VCA region (2, 6, 7). The binding of CDC42, or SH3-containing proteins such as WISH and NCK to the proline-rich domain of N-WASP/WASP alleviates their inhibition by disrupting this intramolecular interaction, leading to the activation of N-WASP and WASP (8 -11). On the other hand, the activity of the WAVE proteins is believed to be regulated by their inclusion in a protein complex that also contains PIR121/NAP1/ Abi/HSPC300, which keeps them in an inactive state (12-16). This inhibition can be lifted by active small GTPases such as GTP-Rac (13), leading to the translocation of the complex to sites of active actin polymerization (14, 16).Phosphorylation of the WASP/WAVE proteins has been shown to regulate their activity (17-21). Phosphorylation of N-WASP/WASP proteins by non-receptor tyrosine kinases, such as ACK1 enhances the ability of WASP to stimulate actin polymerization (22), whereas growth factor stimulation of cultured cells results in hyper-phosphorylation of the WAVE proteins as well as a delay in their mobility in SDS-PAGE (23). WAVE1 was shown to be phosphorylated by the cyclindependent kinase 5 (24), whereas phosphorylation of WAVE2 has recently been shown to involve the non-receptor tyrosine kinase c-Abl (25), resulting in both cases in the stimulation ...

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supporting

confidence: 89%

Section: Discussionmentioning

confidence: 78%

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c-Abl-mediated Phosphorylation of WAVE3 Is Required for Lamellipodia Formation and Cell Migration

Sossey‐Alaoui

Cowell

2007

Journal of Biological Chemistry

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121

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“…This in vitro phenotype was accompanied by a significant decrease of cell migration and invasion, suggesting that WAVE 3 is a critical factor that regulates the motility and adhesiveness of cells. These findings further support, WAVE 3 could also play a vital role in the acquisition of the metastatic potential of tumor cells and this provide an direct evidence for the functional importance of WAVE 3 in tumor cell invasion and metastasis (Sossey et al, 2005). As recently pointed out by Fernando et al, the expression of WAVE 1 and WAVE 3 in prostate cancer cell lines and in prostate tissues respectively, reveals the importance of WAVE 1 and WAVE 3 in controlling the invasiveness of prostate cancer cells (Fernando et al, 2008 and.…”

Section: Wave: Target For Cancer Therapysupporting

confidence: 75%

WAVEs: A Novel and Promising Weapon in the Cancer Therapy Tool Box

Sakthivel¹,

Prabhu²,

Guruvayoorappan³

2012

Asian Pacific Journal of Cancer Prevention

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The Wiskott-Aldrich Syndrome Protein family Verprolin -homologous proteins (WAVEs), encoded by a metastasis promoter gene, play considerable roles in adhesion of immune cells, cell proliferation, migration and destruction of foreign agents by reactive oxygen species. These diverse functions have lead to the hypothesis that WAVE proteins have multi-functional roles in regulating cancer invasiveness, metastasis, development of tumor vasculature and angiogenesis. Differentials in expression of WAVE proteins are associated with a number of neoplasms include colorectal cancer, hepatocellular cancer, lung squamous cell carcinoma, human breast adenocarcinoma and prostate cancer. In this review we attempt to unify our knowledge regarding WAVE proteins, focusing on their potentials as diagnostic markers and molecular targets for cancer therapy.

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“…Secretion of the metalloproteinase MMP-2 has been linked to the expression of Scar1 with Scar1 null or Scar1 RNAi treated MEFs showing decreased secretion of MMP-2 (Suetsugu et al, 2003). In addition, Scar3 (WAVE3) siRNA treatment in MDA-MB-231 cells led to the inhibition of cell migration and a decrease in MMP-1, MMP-9, and PDGFinduced MMP-3 mRNA levels (Sossey-Alaoui et al, 2005). Therefore, we propose that N-WASP is an important activator of the Arp2/3 complex in dorsal ruffles, whereas Scar1 and Scar2 are perhaps more important in controlling subsequent matrix degradation and migration.…”

Section: Discussionmentioning

confidence: 99%

N-WASP Involvement in Dorsal Ruffle Formation in Mouse Embryonic Fibroblasts

Legg

Bompard

Dawson

et al. 2007

MBoC

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The Wiskott-Aldrich syndrome protein (WASP) family activates the Arp2/3 complex leading to the formation of new actin filaments. Here, we study the involvement of Scar1, Scar2, N-WASP, and Arp2/3 complex in dorsal ruffle formation in mouse embryonic fibroblasts (MEFs). Using platelet-derived growth factor to stimulate circular dorsal ruffle assembly in primary E13 and immortalized E9 Scar1 ؉/؉ and Scar1 null MEFs, we establish that Scar1 loss does not impair the formation of dorsal ruffles. Reduction of Scar2 protein levels via small interfering RNA (siRNA) also did not affect dorsal ruffle production. In contrast, wiskostatin, a chemical inhibitor of N-WASP, potently suppressed dorsal ruffle formation in a dose-dependent manner. Furthermore, N-WASP and Arp2 siRNA treatment significantly decreased the formation of dorsal ruffles in MEFs. In addition, the expression of an N-WASP truncation mutant that cannot bind Arp2/3 complex blocked the formation of these structures. Finally, N-WASP ؊/؊ fibroblast-like cells generated aberrant dorsal ruffles. These ruffles were highly unstable, severely depleted of Arp2/3 complex, and diminished in size. We hypothesize that N-WASP and Arp2/3 complex are part of a multiprotein assembly important for the generation of dorsal ruffles and that Scar1 and Scar2 are dispensable for this process.

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WAVE3 promotes cell motility and invasion through the regulation of MMP-1, MMP-3, and MMP-9 expression

Cited by 99 publications

References 53 publications

c-Abl-mediated Phosphorylation of WAVE3 Is Required for Lamellipodia Formation and Cell Migration

c-Abl-mediated Phosphorylation of WAVE3 Is Required for Lamellipodia Formation and Cell Migration

WAVEs: A Novel and Promising Weapon in the Cancer Therapy Tool Box

N-WASP Involvement in Dorsal Ruffle Formation in Mouse Embryonic Fibroblasts

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