Cyfip1 Is a Putative Invasion Suppressor in Epithelial Cancers

Silva, José M.; Ezhkova, Elena; Silva, Javier; Heart, Stephen; Castillo, Maurício; Campos, Yolanda; Castro, Verónica; Bonilla, Félix; Cordon‐Cardo, Carlos; Muthuswamy, Senthil K.; Powers, Scott; Fuchs, Elaine; Hannon, Gregory J.

doi:10.1016/j.cell.2009.04.013

Cited by 79 publications

(102 citation statements)

References 57 publications

(69 reference statements)

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“…For instance, whereas downregulation of Sra1 does not alter cell proliferation, downregulation of the close paralogue Sra2 results in a dramatic reduction in cell proliferation (11). Genetic ablation of Wave2 also results in significant deficiency in proliferation (23), and original data from other Wave complex members suggest a requirement for Wave2/3 and Abi in tumor cell migration and invasion (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

“…The fact that other components of the Wave complex (e.g., Sra1) may act as invasion suppressors (11) suggests that the Wave complex may have different activities depending on the cellular scenario or the protein composition. For instance, whereas downregulation of Sra1 does not alter cell proliferation, downregulation of the close paralogue Sra2 results in a dramatic reduction in cell proliferation (11).…”

Section: Discussionmentioning

confidence: 99%

“…Recent data have suggested an invasion suppressor role for the Wave complex (11). Depletion of Sra1, Nap1, or Wave2 perturbs actin dynamics, reduces epithelial adhesion, and leads to disorganization of tissue architecture.…”

Section: Introductionmentioning

confidence: 99%

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Brick1 Is an Essential Regulator of Actin Cytoskeleton Required for Embryonic Development and Cell Transformation

et al. 2010

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Brick1 (Brk1) is the less-studied component of the Wave/Scar pathway involved in the branched nucleation of actin fibers. The clinical relevance of Brk1 is emphasized by correlative data showing that Von Hippel-Lindau (VHL) patients that also lose the BRK1 gene are protected against the development of tumors. This contrasts with recent evidence suggesting that the Wave complex may function as an invasion suppressor in epithelial cancers. Here, we show that the downregulation of Brk1 results in abnormal actin stress fiber formation and vinculin distribution and loss of Arp2/3 and Wave proteins at the cellular protrusions. Brk1 is required for cell proliferation and cell transformation by oncogenes. In addition, Brk1 downregulation results in defective directional migration and invasive growth in renal cell carcinoma cells as well as in other tumor cell types. Finally, genetic ablation of Brk1 results in dramatic defects in embryo compaction and development, suggesting an essential role for this protein in actin dynamics. Thus, genetic loss or inhibition of BRK1 is likely to be protective against tumor development due to proliferation and motility defects in affected cells. Cancer Res; 70(22); 9349-59.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Brick1 Is an Essential Regulator of Actin Cytoskeleton Required for Embryonic Development and Cell Transformation

et al. 2010

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“…Dysregulation of WAVE complexes might lead to abnormal cellular adhesion and dysregulation of adherens junction formation, as suggested by the loss of CYFIP in several epithelial cancers 77 and our mouse Abi1 knockout studies. 75 Enhanced levels of Abi1 WAVE can also explain the enhanced cell-extracellular matrix adhesion, leading to the progression of leukemia 78,79 and breast cancer.…”

Section: Monographsmentioning

confidence: 99%

Crk and Abi1: Binary Molecular Switches That Regulate Abl Tyrosine Kinase and Signaling to the Cytoskeleton

et al. 2012

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The nonreceptor tyrosine kinases Abl and Arg are among the most well-characterized tyrosine kinases in the human genome. The activation of Abl by N-terminal fusions with Bcr (Bcr-Abl) or Gag (v-Abl) is responsible for chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia and mouse leukemia virus, respectively. In addition, aberrant Abl and Arg activation downstream of several oncogenic growth factor receptors contributes to the development and progression of a variety of human cancers, often associated with poor clinical outcome, drug resistance, and tumor invasion and metastasis. Abl activation can occur by a variety of mechanisms that include domain interactions involving structural remodeling of autoinhibited conformations as well as direct phosphorylation by upstream kinases and phosphatases. Constitutive activation of Abl plays a significant role in regulating the actin cytoskeleton by modulating cell adhesion, motility, and invadopodia. This review addresses the role of Abl and Arg in tumor progression with particular emphasis on the roles of Crk and Abi1 adapter proteins as distinct molecular switches for Abl transactivation. These insights, combined with new insights into the structure of these kinases, provide the rationale to envision that Crk and Abi1 fine-tune Abl regulation to control signaling to the cytoskeleton.

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“…Furthermore, an activating mutation in Rac1, Rac1 P29S, has been linked to disease progression and metastasis in melanoma (Mar et al, 2014), and clearly blocks haptotaxis in fibroblasts in response to fibronectin. Finally, mutations in Cyfip1, a subunit of the WRC, implicate it as an invasion-suppressor protein in epithelial cancer (Silva et al, 2009).…”

Section: The Relevance Of Haptotaxis For Tumor Progression and Metastmentioning

confidence: 99%

Lamellipodia are crucial for haptotactic sensing and response

King

Asokan

Haynes

et al. 2016

Journal of Cell Science

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Haptotaxis is the process by which cells respond to gradients of substrate-bound cues, such as extracellular matrix proteins (ECM); however, the cellular mechanism of this response remains poorly understood and has mainly been studied by comparing cell behavior on uniform ECMs with different concentrations of components. To study haptotaxis in response to gradients, we utilized microfluidic chambers to generate gradients of the ECM protein fibronectin, and imaged the cell migration response. Lamellipodia are fan-shaped protrusions that are common in migrating cells. Here, we define a new function for lamellipodia and the cellular mechanism required for haptotaxisdifferential actin and lamellipodial protrusion dynamics lead to biased cell migration. Modest differences in lamellipodial dynamics occurring over time periods of seconds to minutes are summed over hours to produce differential whole cell movement towards higher concentrations of fibronectin. We identify a specific subset of lamellipodia regulators as being crucial for haptotaxis. Numerous studies have linked components of this pathway to cancer metastasis and, consistent with this, we find that expression of the oncogenic Rac1 P29S mutation abrogates haptotaxis. Finally, we show that haptotaxis also operates through this pathway in 3D environments.

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Cyfip1 Is a Putative Invasion Suppressor in Epithelial Cancers

Cited by 79 publications

References 57 publications

Brick1 Is an Essential Regulator of Actin Cytoskeleton Required for Embryonic Development and Cell Transformation

Brick1 Is an Essential Regulator of Actin Cytoskeleton Required for Embryonic Development and Cell Transformation

Crk and Abi1: Binary Molecular Switches That Regulate Abl Tyrosine Kinase and Signaling to the Cytoskeleton

Lamellipodia are crucial for haptotactic sensing and response

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