Vertebrate Ctr1 coordinates morphogenesis and progenitor cell fate and regulates embryonic stem cell differentiation

Haremaki, Tomomi; Fraser, Stuart T.; Kuo, Yien–Ming; Baron, Margaret H.; Weinstein, Daniel C.

doi:10.1073/pnas.0701413104

Cited by 38 publications

(49 citation statements)

References 44 publications

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“…Our studies are in partial contrast to a previous report which showed reduced Erk phosphorylation in FGF-stimulated Xenopus embryos treated with morpholinos against the Xenopus Ctr1, Xctr1 (20). The authors proposed that this occurs in a Cu ϩ transport-independent fashion and that Ctr1 serves as a scaffold to regulate Mek signaling.…”

Section: Discussioncontrasting

confidence: 99%

“…In contrast to a report suggesting a Cu ϩ transport- Expression of UAS-Ras V12 using an apterous-Gal4 (ap-Gal4) driver, which drives expression in the dorsal compartment of the wing, is lethal, presumably because apterous is also expressed in portions of the central and peripheral parts of the nervous system, while expression of both the UAS-Ras V12 and UAS-Ctr1A independent function for Ctr1 in Ras/MAPK signaling (20), the experimental results presented in Fig. 3 suggest an involvement of Cu in Ras/MAPK signaling.…”

Section: Conservation Of Function Of Ctr1 and Cu In Erk Activation Incontrasting

confidence: 57%

“…Independently, we have confirmed that reduction of Ctr1A protein levels in S2 cells results in decreased Erk phosphorylation (data not shown). An additional study suggests a role for Xenopus Ctr1 in Ras/MAPK signaling whereby Ctr1 functions in a Cu ϩ transport-independent manner as a scaffold protein (20). To explore whether both Ctr1 and the associated Cu ϩ transport function are important for Ras signaling to Erk1/2, Cu ϩ -specific chelation was used to impose Cu deficiency on cultured fly S2 cells.…”

Section: V12mentioning

confidence: 99%

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A Novel Role for Copper in Ras/Mitogen-Activated Protein Kinase Signaling

Turski

Brady

Kim

et al. 2012

Molecular and Cellular Biology

235

218

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c Copper (Cu) is essential for development and proliferation, yet the cellular requirements for Cu in these processes are not well defined. We report that Cu plays an unanticipated role in the mitogen-activated protein (MAP) kinase pathway. Ablation of the Ctr1 high-affinity Cu transporter in flies and mouse cells, mutation of Ctr1, and Cu chelators all reduce the ability of the MAP kinase kinase Mek1 to phosphorylate the MAP kinase Erk. Moreover, mice bearing a cardiac-tissue-specific knockout of Ctr1 are deficient in Erk phosphorylation in cardiac tissue. In vitro investigations reveal that recombinant Mek1 binds two Cu atoms with high affinity and that Cu enhances Mek1 phosphorylation of Erk in a dose-dependent fashion. Coimmunoprecipitation experiments suggest that Cu is important for promoting the Mek1-Erk physical interaction that precedes the phosphorylation of Erk by Mek1. These results demonstrate a role for Ctr1 and Cu in activating a pathway well known to play a key role in normal physiology and in cancer. Copper (Cu) is a metal ion that functions as a redox-active cofactor for a broad range of biochemical reactions, including mitochondrial oxidative phosphorylation, protection from reactive oxygen species, connective tissue maturation, iron absorption, neuropeptide biogenesis, and other processes (28, 43). Numerous studies point to the essentiality of Cu for normal growth and development, while aberrant Cu accumulation in tissues, as manifested in Wilson's disease patients, results in significant pathologies (33,35,42,47,60,61). However, the precise roles Cu plays and the mechanistic processes by which Cu drives cellular proliferation and growth are not well understood.The Ras/mitogen-activated protein kinase (MAPK) signaling pathway is an evolutionarily conserved pathway involved in the control of many fundamental biological processes, including cell proliferation, apoptosis, survival, differentiation, motility, and metabolism (26,30). Aberrant Ras/MAPK signaling has significant consequences; loss of function of several components of the Ras/MAPK signaling cascade results in lethality, whereas gain-offunction mutations in many of the Ras/MAPK signaling components underlie cancer (2,12,26,55).Here we identify the Ctr1 high-affinity Cu ϩ transporter, conserved from yeast to humans, as being important for stimulation of the MAPK Erk in response to extracellular growth factor-mediated activation of the Ras signaling pathway. Moreover, genetic, physiological, and biochemical experiments point to a direct role for Cu in the ability of the MAPK kinase Mek1 to phosphorylate Erk in fruit flies, cultured cells, and mice. These studies suggest that the MAPK signaling pathway is a key cellular proliferation pathway that is stimulated by Cu and may be a direct target of potent cancer chemotherapeutics that function via Cu chelation. MATERIALS AND METHODS Drosophila melanogaster stocks and crosses. Phantom Gal4, UAS mCD8::GFP/TM6, Tb flies were from Michael O'Connor, University of Minnesota (44). The UAS-Ctr1ARNA...

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Section: Discussioncontrasting

confidence: 99%

Section: Conservation Of Function Of Ctr1 and Cu In Erk Activation Incontrasting

confidence: 57%

Section: V12mentioning

confidence: 99%

See 1 more Smart Citation

A Novel Role for Copper in Ras/Mitogen-Activated Protein Kinase Signaling

Turski

Brady

Kim

et al. 2012

Molecular and Cellular Biology

235

218

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“…It is possible that in the absence of FGF4 and FGF8, other FGF ligands are insufficient to activate the pathway; this is analogous to the limb bud, where Fgf4 and Fgf8 are required despite the expression of other FGF ligand genes (17,(28)(29)(30). Alternately, it is possible that other FGFs in the PSM are acting via noncanonical modes of FGF signaling, such as activation of the PLCγ pathway, which do not activate classical FGF signaling markers (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

FGF4 and FGF8 comprise the wavefront activity that controls somitogenesis

Naiche

Holder

Lewandoski

2011

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

157

191

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Somites form along the embryonic axis by sequential segmentation from the presomitic mesoderm (PSM) and differentiate into the segmented vertebral column as well as other unsegmented tissues. Somites are thought to form via the intersection of two activities known as the clock and the wavefront. Previous work has suggested that fibroblast growth factor (FGF) activity may be the wavefront signal, which maintains the PSM in an undifferentiated state. However, it is unclear which (if any) of the FGFs expressed in the PSM comprise this activity, as removal of any one gene is insufficient to disrupt early somitogenesis. Here we show that when both Fgf4 and Fgf8 are deleted in the PSM, expression of most PSM genes is absent, including cycling genes, WNT pathway genes, and markers of undifferentiated PSM. Significantly, markers of nascent somite cell fate expand throughout the PSM, demonstrating the premature differentiation of this entire tissue, a highly unusual phenotype indicative of the loss of wavefront activity. When WNT signaling is restored in mutants, PSM progenitor markers are partially restored but premature differentiation of the PSM still occurs, demonstrating that FGF signaling operates independently of WNT signaling. This study provides genetic evidence that FGFs are the wavefront signal and identifies the specific FGF ligands that encode this activity. Furthermore, these data show that FGF action maintains WNT signaling, and that both signaling pathways are required in parallel to maintain PSM progenitor tissue.genetic redundancy | Spry | T-Cre | axis extension | paraxial mesoderm

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“…For example, the Xenopus copper transporter CTR1 is thought to be a critical component of the membrane-associated FGF signaling complex, transducing FGF signals independently of copper (38). ZnT1 has been shown to regulate Raf1 biological activity, down-regulate transcription factors stimulated by MTF1, c-Jun, and Elk, or inhibit L-type calcium channels by decreasing the trafficking of the L-type calcium channel ␣ 1 -subunit (28,39,40).…”

Section: Discussionmentioning

confidence: 99%

Tissue Nonspecific Alkaline Phosphatase Is Activated via a Two-step Mechanism by Zinc Transport Complexes in the Early Secretory Pathway

Fukunaka

Kurokawa

Teranishi

et al. 2011

Journal of Biological Chemistry

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A number of enzymes become functional by binding to zinc during their journey through the early secretory pathway. The zinc transporters (ZnTs) located there play important roles in this step. We have previously shown that two zinc transport complexes, ZnT5/ZnT6 heterodimers and ZnT7 homo-oligomers, are required for the activation of alkaline phosphatases, by converting them from the apo-to the holo-form. Here, we investigated the molecular mechanisms of this activation. ZnT1 and ZnT4 expressed in chicken DT40 cells did not contribute to the activation of tissue nonspecific alkaline phosphatase (TNAP). The reduced activity of TNAP in DT40 cells deficient in both ZnT complexes was not restored by zinc supplementation nor by exogenous expression of other ZnTs that increase the zinc content in the secretory pathway. Moreover, we showed that expression of ZnT5/ZnT6 heterodimers reconstituted with zinc transport-incompetent ZnT5 mutant failed to restore TNAP activity but could stabilize the TNAP protein as the apo-form, regardless of zinc status. These findings demonstrate that TNAP is activated not simply by passive zinc binding but by an elaborate two-step mechanism via protein stabilization followed by enzyme conversion from the apo-to the holo-form with zinc loaded by ZnT complexes in the early secretory pathway.

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Vertebrate Ctr1 coordinates morphogenesis and progenitor cell fate and regulates embryonic stem cell differentiation

Cited by 38 publications

References 44 publications

A Novel Role for Copper in Ras/Mitogen-Activated Protein Kinase Signaling

A Novel Role for Copper in Ras/Mitogen-Activated Protein Kinase Signaling

FGF4 and FGF8 comprise the wavefront activity that controls somitogenesis

Tissue Nonspecific Alkaline Phosphatase Is Activated via a Two-step Mechanism by Zinc Transport Complexes in the Early Secretory Pathway

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