The Rho GTPase Rif signals through IRTKS, Eps8 and WAVE2 to generate dorsal membrane ruffles and filopodia

Sudhaharan, Thankiah; Sem, Kai Ping; Liew, Hwi Fen; Yu, Yuan Hong; Goh, Wah Ing; Chou, Amy; Ahmed, Sohail

doi:10.1242/jcs.179655

Cited by 24 publications

(36 citation statements)

References 30 publications

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“…IRSp53 and IRTKS are central modulators of actin dynamics downstream of the Rho family of small GTPases Cdc42, Rac1 and Rif281033. Consistent with their activities in mediating major physiological functions through interactions with multiple partners in different pathways, knockout models of Cdc42 and Rac are embryonic lethal at early gestation stages5051.…”

Section: Discussionmentioning

confidence: 94%

“…Similar to IRSp53, IRTKS is phosphorylated upon insulin stimulation and its over-expression in cells leads to actin-rich membrane protrusions330. Notably, IRTKS lacks a Cdc42-interacting domain, but its I-BAR and SH3 domains have been shown to interact with several known IRSp53 partners such as Rac, Eps8 and Shank, suggesting the two proteins may overlap in mediating actin cytoskeletal remodelling induced by growth factor signalling30313233.…”

Section: Resultsmentioning

confidence: 99%

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Redundant functions of I-BAR family members, IRSp53 and IRTKS, are essential for embryonic development

Chou

Sem

Lam

et al. 2017

Sci Rep

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The insulin receptor substrate of 53 kDa, IRSp53, is an adaptor protein that works with activated GTPases, Cdc42 and Rac, to modulate actin dynamics and generate membrane protrusions in response to cell signaling. Adult mice that lack IRSp53 fail to regulate synaptic plasticity and exhibit hippocampus-associated learning deficiencies. Here, we show that 60% of IRSp53 null embryos die at mid to late gestation, indicating a vital IRSp53 function in embryonic development. We find that IRSp53 KO embryos displayed pleiotropic phenotypes such as developmental delay, oligodactyly and subcutaneous edema, and died of severely impaired cardiac and placental development. We further show that double knockout of IRSp53 and its closest family member, IRTKS, resulted in exacerbated placental abnormalities, particularly in spongiotrophoblast differentiation and development, giving rise to complete embryonic lethality. Hence, our findings demonstrate a hitherto under-appreciated IRSp53 function in embryonic development, and further establish an essential genetic interaction between IRSp53 and IRTKS in placental formation.

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Section: Discussionmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Redundant functions of I-BAR family members, IRSp53 and IRTKS, are essential for embryonic development

Chou

Sem

Lam

et al. 2017

Sci Rep

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“…For example, Tir has been shown to interact with the I-BAR domain of BAIAP2L1 to regulate actin pedestal formation (15). Likewise, it was also revealed that Rif colocalizes with BAIAP2L2 that is involved in edge ruffling at cell-cell contacts (16).…”

Section: Introductionmentioning

confidence: 99%

BAI1‑associated protein 2‑like 2 is a potential biomarker in lung cancer

Zhang

et al. 2018

Oncol Rep

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Lung cancer is the leading cause of cancer-related death worldwide. The underlying molecular mechanisms that trigger this disease remain largely unknown. The I-BAR family is involved in regulating cell membrane formation and some members, such as BAIAP2L1, IRSp53 and MIM have been shown to participate in tumorigenic progression. However, the role of BAI1-associated protein 2-like 2 (BAIAP2L2) in cancer development is unclear. In the present study, we determined that BAIAP2L2 was upregulated in lung adenocarcinoma tissues and various lung cancer cell lines. In vitro, BAIAP2L2 silencing resulted in decreased viability and colony formation capacity of both A549 and H1299 cells. By contrast, BAIAP2L2 overexpression promoted the proliferation and growth of 95D cells. These results indicated that BAIAP2L2 was essential for lung cancer cell proliferation and growth. We also found that BAIAP2L2 knockdown increased the apoptosis of A549 and H1299 cells. At the molecular level, BAIAP2L2 knockdown led to dysregulation of numerous genes, among which the Estrogen-mediated S-phase Entry pathway was significantly suppressed. Collectively, our findings revealed BAIAP2L2 as a novel biomarker and potential therapeutic target for lung cancer.

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“…Indeed, the I-BAR domains of both IRTKS and MIM are known to bind to small GTPase Rac1 [22,23], activation of which could lead to activation of Erk1/2. In addition to Rac1, IRTKS was recently reported to interact with small GTPase Rif by its I-BAR domain [24]. Hence, it is quite possible that IRTKS and MIM could bind to different small GTPases, which may influence profoundly their subsequent signaling under different cellular contexts.…”

Section: Discussionmentioning

confidence: 99%

“…These differences could explain specific function of each I-BAR protein. For example, IRTKS induces dorsal membrane ruffles [24] and is associated with invadopodia in cancer cells and podosomes in osteoclasts [26]. In contrast, MIM induces filopodia-like protrusions when it is overexpressed [27].…”

Section: Discussionmentioning

confidence: 99%

The SH3 domain distinguishes the role of I-BAR proteins IRTKS and MIM in chemotactic response to serum

Liu

Baxter

et al. 2016

Biochemical and Biophysical Research Communications

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The family of inverse BAR (I-BAR) domain proteins participates in a range of cellular processes associated with membrane dynamics and consists of five distinct members. Three of the I-BAR proteins, including insulin receptor tyrosine kinase substrate (IRTKS), contain an SH3 domain near their C-termini. Yet, the function of the SH3 domain of IRTKS remains uncharacterized. Here we report that in contrast to MIM, which is a prototype of I-BAR proteins and does not contain an SH3 domain, IRTKS promoted serum-induced cell migration along with enhanced phosphorylation of mitogen activated kinases Erk1/2 and p38, and activation of small GTPases Rac1 and Cdc42. In addition, cells overexpressing IRTKS exhibited an increased polarity characterized by elongated cytoplasm and extensive lamellipodia at leading edges. However, a mutant with deletion of the SH3 domain attenuated both cellular motility and p38 phosphorylation but had little effect on Erk1/2 phosphorylation. Also, a chimeric mutant in which the N-terminal portion of MIM is fused with the C-terminal IRTKS, including the SH3 domain, was able to promote chemotactic response to serum and cellular polarity. In contrast, a chimeric mutant in which the N-terminal IRTKS is fused with the C-terminal MIM failed to do so. Furthermore, treatment of cells with SB203580, a selective inhibitor of p38, also neutralized the effect of IRTKS on cell migration. These data indicate that the SH3 domain distinguishes the function of IRTKS in promoting cell migration and inducing signal transduction from those of SH3-less I-BAR proteins.

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The Rho GTPase Rif signals through IRTKS, Eps8 and WAVE2 to generate dorsal membrane ruffles and filopodia

Cited by 24 publications

References 30 publications

Redundant functions of I-BAR family members, IRSp53 and IRTKS, are essential for embryonic development

Redundant functions of I-BAR family members, IRSp53 and IRTKS, are essential for embryonic development

BAI1‑associated protein 2‑like 2 is a potential biomarker in lung cancer

The SH3 domain distinguishes the role of I-BAR proteins IRTKS and MIM in chemotactic response to serum

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