2014 Vol. 5, No. 7

News and views
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China & Correspondence: zhup@ibp.ac.cn (P. Zhu), liguohong@sun5.ibp.ac.cn (G. Li)
Ping Chen, Ping Zhu, Guohong Li
2014, 5(7): 489-491. doi: 10.1007/s13238-014-0080-x
Why is dimerization essential for class-C GPCR function? New insights from mGluR1 crystal structure analysis
Xuejun C. Zhang, Jianfeng Liu, Daohua Jiang
2014, 5(7): 492-495. doi: 10.1007/s13238-014-0062-z
ROR1, an embryonic protein with an emerging role in cancer biology
Nicholas Borcherding, David Kusner, Guang-Hui Liu, Weizhou Zhang
2014, 5(7): 496-502. doi: 10.1007/s13238-014-0059-7
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the ROR family consisting of ROR1 and ROR2. RORs contain two distinct extracellular cysteinerich domains and one transmembrane domain. Within the intracellular portion, ROR1 possesses a tyrosine kinase domain, two serine/threonine-rich domains and a proline-rich domain. RORs have been studied in the context of embryonic patterning and neurogenesis through a variety of homologs. These physiologic functions are dichotomous based on the requirement of the kinase domain. A growing literature has established ROR1 as a marker for cancer, such as in CLL and other blood malignancies. In addition, ROR1 is critically involved in progression of a number of blood and solid malignancies. ROR1 has been shown to inhibit apoptosis, potentiate EGFR signaling, and induce epithelialmesenchymal transition (EMT). Importantly, ROR1 is only detectable in embryonic tissue and generally absent in adult tissue, making the protein an ideal drug target for cancer therapy.
The regulation of TGF-β/SMAD signaling by protein deubiquitination
Juan Zhang, Xiaofei Zhang, Feng Xie, Zhengkui Zhang, Hans van Dam, Long Zhang, Fangfang Zhou
2014, 5(7): 503-517. doi: 10.1007/s13238-014-0058-8
Transforming growth factor-β (TGF-β) members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-β type Ⅱ (TβR Ⅱ) and type I (TβRI) and serine/threonine kinases receptors. Aberrant activation of TGF-β signaling leads to diseases, including cancer. In advanced cancer, the TGF-β/SMAD pathway can act as an oncogenic factor driving tumor cell invasion and metastasis, and thus is considered to be a therapeutic target. The activity of TGF-β/SMAD pathway is known to be regulated by ubiquitination at multiple levels. As ubiquitination is reversible, emerging studies have uncovered key roles for ubiquitin-removals on TGF-β signaling components by deubiquitinating enzymes (DUBs). In this paper, we summarize the latest findings on the DUBs that control the activity of the TGF-β signaling pathway. The regulatory roles of these DUBs as a driving force for cancer progression as well as their underlying working mechanisms are also discussed.
Mechanomics: an emerging field between biology and biomechanics
Jiawen Wang, Dongyuan Lü, Debin Mao, Mian Long
2014, 5(7): 518-531. doi: 10.1007/s13238-014-0057-9
Cells sense various in vivo mechanical stimuli, which initiate downstream signaling to mechanical forces. While a body of evidences is presented on the impact of limited mechanical regulators in past decades, the mechanisms how biomechanical responses globally affect cell function need to be addressed. Complexity and diversity of in vivo mechanical clues present distinct patterns of shear flow, tensile stretch, or mechanical compression with various parametric combination of its magnitude, duration, or frequency. Thus, it is required to understand, from the viewpoint of mechanobiology, what mechanical features of cells are, why mechanical properties are different among distinct cell types, and how forces are transduced to downstream biochemical signals. Meanwhile, those in vitro isolated mechanical stimuli are usually coupled together in vivo, suggesting that the different factors that are in effect individually could be canceled out or orchestrated with each other. Evidently, omics analysis, a powerful tool in the field of system biology, is advantageous to combine with mechanobiology and then to map the fullset of mechanically sensitive proteins and transcripts encoded by its genome. This new emerging field, namely mechanomics, makes it possible to elucidate the global responses under systematically-varied mechanical stimuli. This review discusses the current advances in the related fields of mechanomics and elaborates how cells sense external forces and activate the biological responses.
Research articles
FXYD6: a novel therapeutic target toward hepatocellular carcinoma
Qian Gao, Xiongfei Chen, Hongxia Duan, Zhaoqing Wang, Jing Feng, Dongling Yang, Lina Song, Ningxin Zhou, Xiyun Yan
2014, 5(7): 532-543. doi: 10.1007/s13238-014-0045-0
FXYD6, FXYD domain containing ion transport regulator 6, has been reported to affect the activity of Na+/K+-ATPase and be associated with mental diseases. Here, we demonstrate that FXYD6 is up-regulated in hepatocellular carcinoma (HCC) and enhances the migration and proliferation of HCC cells. Up-regulation of FXYD6 not only positively correlates with the increase of Na+/K+-ATPase but also coordinates with the activation of its downstream Src-ERK signaling pathway. More importantly, blocking FXYD6 by its functional antibody significantly inhibits the growth potential of the xenografted HCC tumors in mice, indicating that FXYD6 represents a potential therapeutic target toward HCC. Altogether, our results establish a critical role of FXYD6 in HCC progression and suggest that the therapy targeting FXYD6 can benefit the clinical treatment toward HCC patients.
Functional analysis of the acetylation of human p53 in DNA damage responses
Sun-Ku Chung, Shengyun Zhu, Yang Xu, Xuemei Fu
2014, 5(7): 544-551. doi: 10.1007/s13238-014-0048-x
As a critical tumor suppressor, p53 is inactivated in human cancer cells by somatic gene mutation or disruption of pathways required for its activation. Therefore, it is critical to elucidate the mechanism underlying p53 activation after genotoxic and cellular stresses. Accumulating evidence has indicated the importance of posttranslational modifications such as acetylation in regulating p53 stability and activity. However, the physiological roles of the eight identified acetylation events in regulating p53 responses remain to be fully understood. By employing homologous recombination, we introduced various combinations of missense mutations (lysine to arginine) into eight acetylation sites of the endogenous p53 gene in human embryonic stem cells (hESCs). By determining the p53 responses to DNA damage in the p53 knock-in mutant hESCs and their derivatives, we demonstrate physiological importance of the acetylation events within the core domain (K120 and K164) and at the C-terminus (K370/372/373/381/382/386) in regulating human p53 responses to DNA damage.
Development of an activity-directed selection system enabled significant improvement of the carboxylation efficiency of Rubisco
Zhen Cai, Guoxia Liu, Junli Zhang, Yin Li
2014, 5(7): 552-562. doi: 10.1007/s13238-014-0072-x
Photosynthetic CO2 fixation is the ultimate source of organic carbon on earth and thus is essential for crop production and carbon sequestration. Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) catalyzes the first step of photosynthetic CO2 fixation. However, the extreme low carboxylation efficiency of Rubisco makes it the most attractive target for improving photosynthetic efficiency. Extensive studies have focused on re-engineering a more efficient enzyme, but the effort has been impeded by the limited understanding of its structure-function relationships and the lack of an efficient selection system towards its activity. To address the unsuccessful molecular engineering of Rubisco, we developed an Escherichia coli-based activity-directed selection system which links the growth of host cell solely to the Rubisco activity therein. A Synechococcus sp. PCC7002 Rubisco mutant with E49V and D82G substitutions in the small subunit was selected from a total of 15,000 mutants by one round of evolution. This mutant showed an 85% increase in specific carboxylation activity and a 45% improvement in catalytic efficiency towards CO2. The small-subunit E49V mutation was speculated to influence holoenzyme catalysis through interaction with the large-subunit Q225. This interaction is conserved among various Rubisco from higher plants and Chlamydomonas reinhardtii. Knowledge of these might provide clues for engineering Rubisco from higher plants, with the potential of increasing the crop yield.
EF4 knockout E. coli cells exhibit lower levels of cellular biosynthesis under acidic stress
Fang Yang, Zhikai Li, Jia Hao, Yan Qin
2014, 5(7): 563-567. doi: 10.1007/s13238-014-0050-3