Endocytosis of Fgf8 Is a Double-Stage Process and Regulates Spreading and Signaling

Rengarajan, Charanya; Matzke, Alexandra; Reiner, Luisa; Orian-Rousseau, Véronique; Scholpp, Steffen

doi:10.1371/journal.pone.0086373

Cited by 6 publications

(7 citation statements)

References 61 publications

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“…These results indicate that KIT-containing early endosomes can indeed transit KIT signals to the downstream molecules as a signaling endosome. A very recent study showed that Bafilomycin A1, which inhibits protein transport from early to late endosome, enhanced FGF (fibroblast growth factor)-induced activation of ERK1/2 in HEK293 cells [27] . However, in contrast to Akt, we didn’t observe the enhanced phosphprylation of ERK1/2 ( Fig.…”

Section: Discussionmentioning

confidence: 99%

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Clathrin Assembly Protein CALM Plays a Critical Role in KIT Signaling by Regulating Its Cellular Transport from Early to Late Endosomes in Hematopoietic Cells

et al. 2014

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CALM is implicated in the formation of clathrin-coated vesicles, which mediate endocytosis and intracellular trafficking of growth factor receptors and nutrients. We previously found that CALM-deficient mice suffer from severe anemia due to the impaired clathrin-mediated endocytosis of transferrin receptor in immature erythroblast. However, CALM has been supposed to regulate the growth and survival of hematopoietic stem/progenitor cells. So, in this study, we focused on the function of CALM in these cells. We here show that the number of Linage−Sca-1+KIT+ (LSK) cells decreased in the fetal liver of CALM −/− mice. Also, colony forming activity was impaired in CALM−/− LSK cells. In addition, SCF, FLT3, and TPO-dependent growth was severely impaired in CALM−/− LSK cells, while they can normally proliferate in response to IL-3 and IL-6. We also examined the intracellular trafficking of KIT using CALM −/− murine embryonic fibroblasts (MEFs) engineered to express KIT. At first, we confirmed that endocytosis of SCF-bound KIT was not impaired in CALM −/− MEFs by the internalization assay. However, SCF-induced KIT trafficking from early to late endosome was severely impaired in CALM −/− MEFs. As a result, although intracellular KIT disappeared 30 min after SCF stimulation in wild-type (WT) MEFs, it was retained in CALM −/− MEFs. Furthermore, SCF-induced phosphorylation of cytosolic KIT was enhanced and prolonged in CALM −/− MEFs compared with that in WT MEFs, leading to the excessive activation of Akt. Similar hyperactivation of Akt was observed in CALM −/− KIT+ cells. These results indicate that CALM is essential for the intracellular trafficking of KIT and its normal functions. Also, our data demonstrate that KIT located in the early endosome can activate downstream molecules as a signaling endosome. Because KIT activation is involved in the pathogenesis of some malignancies, the manipulation of CALM function would be an attractive therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

“…(Rocky Hill, NJ). Imatinib mesylate (STI571) purchased from Selleck (Houston, TX) was used to inhibit KIT activity and Bafilomycin A1 purchased from Sigma Aldrich (St. Louis, MO) was used to inhibit the protein transport from early to late endosome [27] .…”

Section: Methodsmentioning

confidence: 99%

Clathrin Assembly Protein CALM Plays a Critical Role in KIT Signaling by Regulating Its Cellular Transport from Early to Late Endosomes in Hematopoietic Cells

et al. 2014

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“…For fluorescence analysis in zebrafish, the following plasmids were used: xWnt5a (16), zf Fz7-CFP (36), xRor2-mCherry, xWnt5a-GFP (37), mem-mCherry, and GFP-GPI (38). For immunohistochemistry of DMZ explants, Xenopus embryos were injected into the dorsal equatorial zone at the four-cell stage, and DMZ explants were dissected from gastrula embryos at stage 10.…”

Section: Methodsmentioning

confidence: 99%

Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt Signaling from Fz7 to Ror2 during Vertebrate Gastrulation

Brinkmann

Mattes

Kumar

et al. 2016

Journal of Biological Chemistry

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Convergent extension movements during vertebrate gastrulation require a balanced activity of non-canonical Wnt signaling pathways, but the factors regulating this interplay on the molecular level are poorly characterized. Here we show that sFRP2, a member of the secreted frizzled-related protein (sFRP) family, is required for morphogenesis and papc expression during Xenopus gastrulation. We further provide evidence that sFRP2 redirects non-canonical Wnt signaling from Frizzled 7 (Fz7) to the receptor tyrosine kinase-like orphan receptor 2 (Ror2). During this process, sFRP2 promotes Ror2 signal transduction by stabilizing Wnt5a-Ror2 complexes at the membrane, whereas it inhibits Fz7 signaling, probably by blocking Fz7 receptor endocytosis. The cysteine-rich domain of sFRP2 is sufficient for Ror2 activation, and related sFRPs can substitute for this function. Notably, direct interaction of the two receptors via their cysteine-rich domains also promotes Ror2-mediated papc expression but inhibits Fz7 signaling. We propose that sFRPs can act as a molecular switch, channeling the signal input for different non-canonical Wnt pathways during vertebrate gastrulation.

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“…The strength of FGF8 signal in the mesoderm is controlled by a double-step process of endocytosis. 46 , 49 The signaling strength of FGF8 in mesodermal cells is dependent on the rate of this endocytosis. In the first step, an invagination in the cell membrane occurs around the activated FGF8–FGFR1 complex.…”

Section: Epidemiologymentioning

confidence: 99%

The Classification of VACTERL Association into 3 Groups According to the Limb Defect

Al‐Qattan

2021

Plastic and Reconstructive Surgery - Global Open

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Summary: The VACTERL association (VA) is defined as the nonrandom co-occurrence of 6 anomalies: vertebral anomalies (V), Anal atresia (A), Cardiac defects (C), Tracheo-esophageal fistula (TE), Renal defects (R), and Limb anomalies (L). The current communication presents an argument that patients with VA should be classified into three district groups based on their limb defects: VACTERL1: patients with normal limbs; VACTERL2: patients with limb anomalies other than radial ray defects of the upper limbs; and VACTERL3: patients with radial ray defects of the upper limbs. The author will demonstrate that the rationale behind the L1-3 classification in patients in VA is based on the embryogenesis of the 6 affected anatomical areas in VA. The pathogenesis of VACTERL1 is secondary to perturbations of Sonic Hedgehog (SHH) interactions. SHH signaling is known to have a major role in the normal development of the vertebrae, ano-rectal area, heart, tracheo-esophageal area, and kidney. However, SHH is not involved in the development of the radial ray; hence, patients present with no limb defects. The pathogenesis of VACTERL2 is variable depending on the type of gene mutation. The pathogenesis of VACTERL3 is related to errors in a group of proteins (namely, the proteins of the TBX5-SALL4-SALL1 loop and the FGF8-FGF10 loop/ pathway). These proteins are essential for the normal development of the radial ray and they interact in the development of the other anatomical areas of VA including the heart and kidney. Hence, VACTERL3 patients present with radial ray deficiency.

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Endocytosis of Fgf8 Is a Double-Stage Process and Regulates Spreading and Signaling

Cited by 6 publications

References 61 publications

Clathrin Assembly Protein CALM Plays a Critical Role in KIT Signaling by Regulating Its Cellular Transport from Early to Late Endosomes in Hematopoietic Cells

Clathrin Assembly Protein CALM Plays a Critical Role in KIT Signaling by Regulating Its Cellular Transport from Early to Late Endosomes in Hematopoietic Cells

Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt Signaling from Fz7 to Ror2 during Vertebrate Gastrulation

The Classification of VACTERL Association into 3 Groups According to the Limb Defect

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