SH3YL1 regulates dorsal ruffle formation by a novel phosphoinositide-binding domain

Hasegawa, Junya; Tokuda, Emi; Tenno, Takeshi; Tsujita, Kazuya; Sawai, Haruko; Hiroaki, Hidekazu; Takenawa, Tadaomi; Itoh, Toshiki

doi:10.1083/jcb.201012161

Cited by 84 publications

(126 citation statements)

References 51 publications

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“…We then found that INPP4B, which dephosphorylates PI(3,4)P 2 to PI(3)P, is also required for macropinocytosis. It has been reported that SHIP2, which dephosphorylates PI(3,4,5)P 3 to PI(3,4)P 2 , is required for macropinocytosis (17). Together, these findings suggest that macropinocytosis is controlled by the sequential breakdown of PI(3,4,5)P 3 → PI(3,4)P 2 → PI(3)P → PI in the PM.…”

Section: Significancesupporting

confidence: 50%

“…3C), indicating that the PHG domains are necessary and sufficient for targeting of MTMR6/ MTMR9 to membrane ruffles. Recent studies have shown that PI(3,4,5)P 3 and PI(3,4)P 2 are transiently generated in membrane ruffles and dissipated during macropinocytosis (17)(18)(19)(20). Moreover, PI3K and 5-phosphatase SHIP2 have been shown to be required for macropinocytosis through phosphorylation of PI(4,5)P 2 and dephosphorylation of PI(3,4,5)P 3 , respectively (Fig.…”

Section: Mtmr6 and Mtmr9 Are Recruited To Membrane Ruffles Upon Egfmentioning

confidence: 99%

“…Inhibitors of phosphoinositide 3-kinases (PI3Ks), which generate PI(3,4,5)P 3 from PI (4,5)P 2 , impair macropinosome formation (16). Knockdown of 5-phosphatase SH2-domain containing inositol-5-phosphatase 2 (SHIP2), which dephosphorylates PI(3,4,5)P 3 to PI(3,4)P 2 , suppresses macropinocytic uptake of extracellular solutes (17). The dynamic nature of phosphoinositides during macropinocytosis has been described.…”

mentioning

confidence: 99%

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Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis

Maekawa

Shimpei²,

Mochizuki

et al. 2014

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

103

113

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Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and solutes are internalized into cells. Macropinocytosis starts with the formation of membrane ruffles at the plasma membrane and ends with their closure. The transient and sequential emergence of phosphoinositides PI(3,4,5)P 3 and PI(3,4) P 2 in the membrane ruffles is essential for macropinocytosis. By making use of information in the Caenorhabditis elegans mutants defective in fluid-phase endocytosis, we found that mammalian phosphoinositide phosphatase MTMR6 that dephosphorylates PI(3)P to PI, and its binding partner MTMR9, are required for macropinocytosis. INPP4B, which dephosphorylates PI(3,4)P 2 to PI(3)P, was also found to be essential for macropinocytosis. These phosphatases operate after the formation of membrane ruffles to complete macropinocytosis. Finally, we showed that KCa3.1, a Ca 2+ -activated K + channel that is activated by PI(3)P, is required for macropinocytosis. We propose that the sequential breakdown of PI(3,4,5)P 3 → PI(3,4)P 2 → PI(3)P → PI controls macropinocytosis through specific effectors of the intermediate phosphoinositides.

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Section: Significancesupporting

confidence: 50%

Section: Mtmr6 and Mtmr9 Are Recruited To Membrane Ruffles Upon Egfmentioning

confidence: 99%

mentioning

confidence: 99%

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Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis

Maekawa

Shimpei²,

Mochizuki

et al. 2014

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

103

113

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“…lamin A/C and PR130-PP2A) may be critical in targeting SHIP2 to the nucleus [22]. This possibility is very likely as multiple SHIP1/2 phosphosites are found in close proximity to the proline-rich sequences mediating interaction with other proteins: SH3 domain-containing Ysc84-like 1 (SH3YL1) is a protein that regulates dorsal ruffle formation, cell polarity and internalization of cell surface receptors [54]. It interacts with the proline-rich sequence of SHIP2 located N-terminally in the sequence (residues 139-144 of human SHIP2).…”

Section: W Elong Edimo Et Almentioning

confidence: 99%

“…Insights & Perspectives ..... PDGFR [28] p130Cas [70] Vinexin [76] PR130 [47] FcgRIIB [64] p85a [62] Filamin [77] SHIP1 [82] FcgRIIA [65] APS [71] Actin [77] M-CSFR [66] DOK-1 [72] Intersectin1 [78] cMET [67] JIP-1 [73] ARAP-3 [79] ABL [62] CD2AP [74] CIN-85 [80] EphrinA2R [68] SH3YL1 [54] Lamin A/C [22] JIP-1, JNK-interacting protein 1; PTP1B, protein-tyrosine phosphatase 1B; CD2AP, CD2-associated protein; SH3YL1, SH3 domain-containing Ysc84-like 1; PDGFR, platelet-derived growth factor receptor; EGFR, epidermal growth factor receptor; M-CSFR, macrophage colony-stimulating factor receptor; cMET, hepatocyte growth factor (HGF/SF) receptor; EphrinA2R, ephrinA2 receptor; ARAP-3, Arf GAP, Rho GAP, ankyrin repeat and PH domains. It is proposed that SHIP2 is phosphorylated to phospho SHIP2 (pSHIP2) S132 in the cytoplasm.…”

Section: W Elong Edimo Et Almentioning

confidence: 99%

Reversible Ser/Thr SHIP phosphorylation: A new paradigm in phosphoinositide signalling?

et al. 2012

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Phosphoinositide (PI) phosphatases such as the SH2 domain-containing inositol 5-phosphatases 1/2 (SHIP1 and 2) are important signalling enzymes in human physiopathology. SHIP1/2 interact with a large number of immune and growth factor receptors. Tyrosine phosphorylation of SHIP1/2 has been considered to be the determining regulatory modification. However, here we present a hypothesis, based on recent key publications, highlighting the determining role of Ser/Thr phosphorylation in regulating several key properties of SHIP1/2. Since a subunit of the Ser/Thr phosphatase PP2A has been shown to interact with SHIP2, a putative mechanism for reversing SHIP2 Ser/Thr phosphorylation can be anticipated. PI phosphatases are potential target molecules in human diseases, particularly, but not exclusively, in cancer and diabetes. Therefore, this novel regulatory mechanism deserves further attention in the hunt for discovering novel or complementary therapeutic strategies. This mechanism may be more broadly involved in regulating PI signalling in the case of synaptojanin1 or the phosphatase, tensin homolog, deleted on chromosome TEN.

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Phosphoinositide Conversion Inactivates R‐RAS and Drives Metastases in Breast Cancer

Prever

Hsu

et al. 2022

Advanced Science

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Breast cancer is the most prevalent cancer and a major cause of death in women worldwide. Although early diagnosis and therapeutic intervention significantly improve patient survival rate, metastasis still accounts for most deaths. Here it is reported that, in a cohort of more than 2000 patients with breast cancer, overexpression of PI3KC2α occurs in 52% of cases and correlates with high tumor grade as well as increased probability of distant metastatic events, irrespective of the subtype. Mechanistically, it is demonstrated that PI3KC2α synthetizes a pool of PI(3,4)P2 at focal adhesions that lowers their stability and directs breast cancer cell migration, invasion, and metastasis. PI(3,4)P2 locally produced by PI3KC2α at focal adhesions recruits the Ras GTPase activating protein 3 (RASA3), which inactivates R‐RAS, leading to increased focal adhesion turnover, migration, and invasion both in vitro and in vivo. Proof‐of‐concept is eventually provided that inhibiting PI3KC2α or lowering RASA3 activity at focal adhesions significantly reduces the metastatic burden in PI3KC2α‐overexpressing breast cancer, thereby suggesting a novel strategy for anti‐breast cancer therapy.

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SH3YL1 regulates dorsal ruffle formation by a novel phosphoinositide-binding domain

Abstract: The newly identified SYLF lipid-binding domain of SH3YL1 mediates phosphoinositide binding during dorsal membrane morphogenesis.

Cited by 84 publications

References 51 publications

Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis

Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis

Reversible Ser/Thr SHIP phosphorylation: A new paradigm in phosphoinositide signalling?

Phosphoinositide Conversion Inactivates R‐RAS and Drives Metastases in Breast Cancer

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