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11.
Ami Ketley Anne Warren Emily Holmes Martin Gering A. Aziz Aboobaker J. David Brook 《PloS one》2013,8(6)
The importance of microRNAs in development is now widely accepted. However, identifying the specific targets of individual microRNAs and understanding their biological significance remains a major challenge. We have used the zebrafish model system to evaluate the expression and function of microRNAs potentially involved in muscle development and study their interaction with predicted target genes. We altered expression of the miR-30 microRNA family and generated phenotypes that mimicked misregulation of the Hedgehog pathway. Inhibition of the miR-30 family increases activity of the pathway, resulting in elevated ptc1 expression and increased numbers of superficial slow-muscle fibres. We show that the transmembrane receptor smoothened is a target of this microRNA family. Our results indicate that fine coordination of smoothened activity by the miR-30 family allows the correct specification and differentiation of distinct muscle cell types during zebrafish embryonic development. 相似文献
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Yusuke Shiromoto Satomi Kuramochi-Miyagawa Akito Daiba Shinichiro Chuma Ami Katanaya Akiko Katsumata Ken Nishimura Manami Ohtaka Mahito Nakanishi Toshinobu Nakamura Koichi Yoshinaga Noriko Asada Shota Nakamura Teruo Yasunaga Kanako Kojima-Kita Daisuke Itou Tohru Kimura Toru Nakano 《RNA (New York, N.Y.)》2013,19(6):803-810
piRNA (PIWI-interacting RNA) is a germ cell–specific small RNA in which biogenesis PIWI (P-element wimpy testis) family proteins play crucial roles. MILI (mouse Piwi-like), one of the three mouse PIWI family members, is indispensable for piRNA production, DNA methylation of retrotransposons presumably through the piRNA, and spermatogenesis. The biogenesis of piRNA has been divided into primary and secondary processing pathways; in both of these MILI is involved in mice. To analyze the molecular function of MILI in piRNA biogenesis, we utilized germline stem (GS) cells, which are derived from testicular stem cells and possess a spermatogonial phenotype. We established MILI-null GS cell lines and their revertant, MILI-rescued GS cells, by introducing the Mili gene with Sendai virus vector. Comparison of wild-type, MILI-null, and MILI-rescued GS cells revealed that GS cells were quite useful for analyzing the molecular mechanisms of piRNA production, especially the primary processing pathway. We found that glycerol-3-phosphate acyltransferase 2 (GPAT2), a mitochondrial outer membrane protein for lysophosphatidic acid, bound to MILI using the cells and that gene knockdown of GPAT2 brought about impaired piRNA production in GS cells. GPAT2 is not only one of the MILI bound proteins but also a protein essential for primary piRNA biogenesis. 相似文献
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ErbB-2/HER2 is an oncogenic tyrosine kinase that regulates a signalling network by forming ligand-induced heterodimers with several growth factor receptors of the ErbB family. Hsp90 and co-chaperones regulate degradation of ErbB-2 but not other ErbB members. Here, we report that the role of Hsp90 in modulating the ErbB network extends beyond regulation of protein stability. The capacity of ErbB-2 to recruit ligand-bound receptors into active heterodimers is limited by Hsp90, which is dissociated from ErbB-2 following ligand-induced heterodimerization. We show that Hsp90 binds a specific loop within the kinase domain of ErbB-2, thereby restraining heterodimer formation and catalytic function. These results define a role for Hsp90 as a molecular switch regulating the ErbB signalling network by limiting formation of ErbB-2-centred receptor complexes. 相似文献
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Epidermal growth factor (EGF) stimulation of prostate metastatic tumor cells results in transient phosphorylation and cellular localization of non-muscle myosin heavy chain II-B (NMHC II-B) with kinetics similar to those seen in chemotaxis. We demonstrate that expression of 18- and 72-kDa fragments derived from the NMHC II-B C terminus that contain EGF-dependent NMHC II-B phosphorylation sites serve as dominant-negative mutations for EGF-dependent NMHC II-B phosphorylation and localization. Both fragments inhibited the EGF-dependent phosphorylation by competing with NMHC II-B on the myosin heavy chain kinase. However, only expression of the 72-kDa fragment resulted in cells with abnormalities in cell shape, focal adhesions, and chemotaxis. We found that the 72-kDa (but not 18-kDa) fragment is capable of self-assembly. To our knowledge, these results provide the first strong evidence that EGF-dependent NMHC II-B phosphorylation is required for the cellular localization of NMHC II-B and that NMHC II-B is required for normal cell attachment and for chemotactic response. 相似文献
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Conticello SG Kowalsman ND Jacobsen C Yudkovsky G Sato K Elazar Z Petersen CM Aronheim A Fainzilber M 《The Journal of biological chemistry》2003,278(29):26311-26314
Misfolded secretory proteins are retained in the endoplasmic reticulum (ER) by quality control mechanisms targeted to exposed hydrophobic surfaces. Paradoxically, certain conotoxins expose extensive hydrophobic surfaces upon folding to their bioactive structures. How then can such secreted mini-proteins traverse the secretory pathway? Here we show that secretion of the hydrophobic conotoxin-TxVI is strongly dependent on its propeptide domain, which enhances TxVI export from the ER. The propeptide domain interacts with sorting receptors from the sortilin Vps10p domain family. The sortilin-TxVI interaction occurs in the ER, and sortilin facilitates export of TxVI from the ER to the Golgi. Thus, the prodomain in a secreted hydrophobic protein acts as a tag that can facilitate its ER export by a hitchhiking mechanism. 相似文献
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On the basis of the coordinates of the related Newcastle disease virus (NDV) F protein, Valine-94, a determinant of measles virus (MV) cytopathicity, is predicted to lie in a cylindrical cavity with 10 A diameter located at the F neck. A 16-residue domain around V94 is functionally interchangeable between NDV and MV F, supporting our homology model. Features of the cavity are conserved within the Paramyxovirinae. A hydrophobic base and a hydrophilic residue at the rim are required for surface expression. Small residue substitutions predicted to open the cavity were found to disrupt transport or limit fusogenicity of transport-competent mutants but can be compensated for by simultaneous insertion of larger residues at the opposing wall. Variants containing histidine substitutions mediate fusion at pH 8.5, while at pH 7.2 fusion is blocked, suggesting that functionality requires low charge in the cavity. These results indicate that specific structural features of the cavity are essential for paramyxovirus fusion initiation. 相似文献