Extended-Synaptotagmin-2 Mediates FGF Receptor Endocytosis and ERK Activation In Vivo

Jean, Steve; Mikryukov, Alexander; Tremblay, Michel G.; Baril, Joëlle; Guillou, F.; Bellenfant, Sabrina; Moss, Tom

doi:10.1016/j.devcel.2010.08.007

Cited by 62 publications

(65 citation statements)

References 70 publications

(84 reference statements)

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“…Recent data demonstrated that the ESyts can probably heterodimerize and homodimerize (6,11). Consistent with this, when differentially tagged versions of the three ESyts were expressed in homologous and heterologous pairs, it was evident that not only did all three heterodimerize, but also homodimerize (Fig.…”

Section: Methodssupporting

confidence: 53%

“…Construction of the human ESyt2b splice variant cDNA was previously described (6) and was equivalent in reading frame sequence to FAM62B (NM_020728). The open reading frame for the human ESyt2a splice variant was created from the ESyt2b cDNA by replacing the sequences 5Ј of the unique SacII site with a synthetic custom gene fragment (Integrated DNA Technologies, IDT) corresponding to the equivalent region of sequence DQ993201.…”

Section: Methodsmentioning

confidence: 99%

“…Coimmunoprecipitation-HEK293T cells were processed for co-immunoprecipitation as previously described (6). Briefly, 20 g of anti-HA (12CA5) and 20 l of a slurry of Protein A-Sepharose (GE Healthcare), or 20 l of anti-FLAG agarose beads (Sigma), prepared following manufacturer's instructions was added to the lysates and incubated at 4°C for 2 h. Bound proteins were eluted with 2ϫ SDS-PAGE loading buffer, fractionated on Tris-glycine SDS-PAGE gels, transferred to nitrocellulose membrane (Bio-Rad) and probed with the appropriate antibody.…”

Section: Methodsmentioning

confidence: 99%

“…Human ESyt2 and ESyt3 each contain three C2 domains (C2A, C2B, and C2C) while ESyt1 has five (C2A to C2E) (Fig. 1A), and this organization is conserved in mouse (5), Xenopus (6) and to a surprising extent in the yeast Tricalbins (7).…”

Section: We Previously Demonstrated That Esyt2 Interacts Specificallymentioning

confidence: 99%

“…Jean et al (6) provided the first potential function for ESyt2 when they showed that it acted as an endocytic adapter specific for the activated FGF receptor and was required for functional signaling via the ERK MAP-kinase pathway during early Xenopus development. Xenopus ESyt2 was also later shown to recruit the p21-GTPase Activated Kinase PAK1 and to regulate the dynamics of the actin cytoskeleton (8).…”

Section: We Previously Demonstrated That Esyt2 Interacts Specificallymentioning

confidence: 99%

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Extended Synaptotagmin Interaction with the Fibroblast Growth Factor Receptor Depends on Receptor Conformation, Not Catalytic Activity

Tremblay¹,

Herdman²,

Guillou³

et al. 2015

Journal of Biological Chemistry

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Background: Extended Synaptotagmins selectively bind the active FGF receptor but the mechanism is unknown. Results: ESyt2 and 3 but not ESyt1 recognize the active conformation of the FGF receptor independently of catalytic activity. Conclusion: ESyt2 and probably ESyt3 access the active cleft of the FGFR1 kinase domain. Significance: How ESyts recognize FGFRs is essential to understanding how they modulate receptor signaling.

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Section: Methodssupporting

confidence: 53%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: We Previously Demonstrated That Esyt2 Interacts Specificallymentioning

confidence: 99%

Section: We Previously Demonstrated That Esyt2 Interacts Specificallymentioning

confidence: 99%

See 3 more Smart Citations

Extended Synaptotagmin Interaction with the Fibroblast Growth Factor Receptor Depends on Receptor Conformation, Not Catalytic Activity

Tremblay¹,

Herdman²,

Guillou³

et al. 2015

Journal of Biological Chemistry

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FGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization

et al. 2020

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Fibroblast growth factor receptor 1 (FGFR1) transmits signals through the plasma membrane regulating essential cellular processes like division, motility, metabolism, and death. Overexpression of FGFR1 is observed in numerous tumors and thus constitutes an attractive molecular target for selective cancer treatment. Targeted anti‐cancer therapies aim for the precise delivery of drugs into cancer cells, sparing the healthy ones and thus limiting unwanted side effects. One of the key steps in targeted drug delivery is receptor‐mediated endocytosis. Here, we show that the efficiency and the mechanism of FGFR1 internalization are governed by the spatial distribution of the receptor in the plasma membrane. Using engineered antibodies of different valency, we demonstrate that dimerization of FGFR1 with bivalent antibody triggers clathrin‐mediated endocytosis (CME) of the receptor. Clustering of FGFR1 into larger oligomers with tetravalent antibody stimulates fast and highly efficient uptake of the receptor that occurs via two distinct mechanisms: CME and dynamin‐dependent clathrin‐independent endocytic routes. Furthermore, we show that all endocytic pathways engaged in FGFR1 internalization do not require receptor activation. Our data provide novel insights into the mechanisms of intracellular trafficking of FGFR1 and constitute guidelines for development of highly internalizing antibody‐based drug carriers for targeted therapy of FGFR1‐overproducing cancers.

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Syndesome Therapeutics for Enhancing Diabetic Wound Healing

Singh

Majid

et al. 2016

Adv Healthcare Materials

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Chronic wounds represent a major healthcare and economic problem worldwide. Advanced wound dressings that incorporate bioactive compounds have great potential for improving outcomes in patients with chronic wounds but significant challenges in designing treatments that are effective in long-standing, non-healing wounds. Here, we developed an optimized wound healing gel that delivers syndecan-4 proteoliposomes (“syndesomes”) with FGF-2 to enhance diabetic wound healing. In vitro studies demonstrated that syndesomes markedly increased migration of keratinocytes and fibroblasts isolated from both non-diabetic and diabetic donors. In addition, syndesome treatment led to increased endocytic processing of FGF-2 that included enhanced recycling of FGF-2 to the cell surface after uptake. The optimized syndesome formulation was incorporated into an alginate wound dressing and tested in a splinted wound model in diabetic, ob/ob mice. We found that wounds treated with syndesomes and FGF-2 had markedly enhanced wound closure in comparison to wounds treated with only FGF-2. Moreover, we show that syndesomes have an immunomodulatory effect on wound macrophages, leading to a shift towards the M2 macrophage phenotype and alterations in the wound cytokine profile. Together, these studies showed that delivery of exogenous syndecan-4 is an effective method for enhancing wound healing in the long-term diabetic diseased state.

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Extended-Synaptotagmin-2 Mediates FGF Receptor Endocytosis and ERK Activation In Vivo

Cited by 62 publications

References 70 publications

Extended Synaptotagmin Interaction with the Fibroblast Growth Factor Receptor Depends on Receptor Conformation, Not Catalytic Activity

Extended Synaptotagmin Interaction with the Fibroblast Growth Factor Receptor Depends on Receptor Conformation, Not Catalytic Activity

FGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization

Syndesome Therapeutics for Enhancing Diabetic Wound Healing

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