From the Cover: FERONIA receptor-like kinase regulates RHO GTPase signaling of root hair development

Plant RHO GTPases (RAC/ROPs) mediate multiple extracellular signals ranging from hormone to stress and regulate diverse cellular processes important for polarized cell growth, differentiation, development, reproduction, and responses to the environment. They shuttle between the GDP-bound inactive state and the GTP-bound activated state and their activation is predominantly mediated by a family of guanine nucleotide exchange factors (GEFs) referred to as ROPGEFs. Using the Arabidopsis ROPGEF1 as bait, we identified members of a receptor-like kinase (RLK) family as potential upstream regulators for RAC/ROP signaling. NADPH oxidase-derived reactive oxygen species (ROS) are emerging as important regulators for growth and development and play a crucial role in mediating RAC/ROP-regulated root hair development, a polarized cell growth process. We therefore screened T-DNA insertion mutants in these RLKs for root hair defects and found that mutations in one of them, At3g51550 encoding the FERONIA (FER) receptor-like kinase, induced severe root hair defects. We show that the fer phenotypes correlated with reduced levels of active RAC/ROPs and NADPH oxidase-dependent, auxin-regulated ROS accumulation in roots and root hairs and that up-regulating RAC/ROP signaling in fer countered the mutant phenotypes. Taken together, these observations strongly support FER as an upstream regulator for the RAC/ROP-signaled pathway that controls ROS-mediated root hair development. Moreover, FER was pulled down by ROP2 GTPase in a guanine nucleotide-regulated manner implying a dynamic signaling complex involving FER, a ROPGEF, and a RAC/ROP.     

Distribution of resting and ligand-bound ErbB1 and ErbB2 receptor tyrosine kinases in living cells using number and brightness analysis

Ligand-driven dimerizations of ErbB receptor subunits fulfill a fundamental role in their activation. We have used the number and brightness analysis technique to investigate the existence of preformed ligand-independent dimers and clusters and to characterize the initial steps in the activation of ErbB1 and ErbB2. In cells expressing 50,000–200,000 receptors, ErbB1 was monomeric in the absence of ligand stimulation, whereas in CHO cells with receptor levels > 500,000 as much as 30% of ErbB1 was present as preformed dimers. EGF induced the formation of ErbB1 dimers as well as larger clusters (up to pentamers) that colocalized with clathrin-coated pits. The distribution of unstimulated ErbB2 in cells expressing 3·10⁵ - 10⁶ receptors was fundamentally different, in that this receptor was present in preformed homoassociated aggregates containing 5–10 molecules. These constitutive ErbB2 homoclusters colocalized with caveolae, increased in size at subphysiological temperatures, but decreased in size upon EGF stimulation. We conclude that these ErbB2 clusters are promoted primarily by membrane-mediated interactions and are dispersed upon ligand stimulation.     

The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded

The Hippo signaling pathway regulates organ size and tissue homeostasis from Drosophila to mammals. At the core of the Hippo pathway is a kinase cascade extending from the Hippo (Hpo) tumor suppressor to the Yorkie (Yki) oncoprotein. The Hippo kinase cascade, in turn, is regulated by apical membrane-associated proteins such as the FERM domain proteins Merlin and Expanded (Ex), and the WW- and C2-domain protein Kibra. How these apical proteins are themselves regulated remains poorly understood. Here, we identify the transmembrane protein Crumbs (Crb), a determinant of epithelial apical-basal polarity in Drosophila embryos, as an upstream component of the Hippo pathway in imaginal disk growth control. Loss of Crb leads to tissue overgrowth and target gene expression characteristic of defective Hippo signaling. Crb directly binds to Ex through its juxtamembrane FERM-binding motif (FBM). Loss of Crb or mutation of its FBM leads to mislocalization of Ex to basolateral domain of imaginal disk epithelial cells. These results shed light on the mechanism of Ex regulation and provide a molecular link between apical-basal polarity and tissue growth. Furthermore, our studies implicate Crb as a putative cell surface receptor for Hippo signaling by uncovering a transmembrane protein that directly binds to an apical component of the Hippo pathway.     

Insulin Signaling: A Possible Pathogenesis of Cardiac Hypertrophy

Cardiac hypertrophy is one of the most commonly cardiovascular diseases in clinical practice. Despite the extensive studies, the pathophysiology of cardiac hypertrophy, however, remains incompletely understood. Studies have demonstrated that insulin signaling may be involved in cardiac growth and protein synthesis. More recently, a growing body of evidence suggests that insulin signaling is associated with the development of cardiac hypertrophy. The evidence for the hypotheses included that (1) several studies have demonstrated insulin is an important regulator of physiological cardiac growth; (2) PI3K–Akt pathway has been investigated as a participant in the cardiac hypertrophic program; (3) negative regulators of insulin signaling show beneficial effects on cardiac hypertrophy development; and (4) insulin signaling interaction with angiotensin II in cardiac hypertrophy. Although the studies suggest that the association between insulin signaling and cardiac hypertrophy, the exact pathogenesis of insulin signaling in cardiac hypertrophy development remains elusive and requires further investigation. Insulin signaling may provide a scientific basis for further research on the underlying mechanisms of cardiac hypertrophy and may target for pharmacological interruption of cardiac hypertrophy.     

肝复康对肝纤维化大鼠肝组织JAK2和STAT3表达的影响

目的观察中药肝复康对肝纤维化大鼠肝组织Janus激酶2（JAK2）及信号转导子和转录激活子3（STAT3）表达的影响,并对其在JAK2/STAT3信号通路上治疗肝纤维化的作用机制进行初步探讨。方法采用10%四氯化碳皮下注射制备肝纤维化模型,于造模第9周给予肝复康治疗12周。通过测定血清中ALT、AST活性及白蛋白和总蛋白的含量来反映肝脏功能,HE染色法观察肝组织病理学变化,RT-PCR观察JAK2和STAT3 mR-NA的表达。结果经肝复康治疗后,中剂量治疗组与模型组相比较,肝脏的组织学和血清学指标均明显改善,肝组织JAK2、STAT3 mRNA的表达显著减少（P〈0.01）。结论 （1）JAK2/STAT3信号通路在肝纤维化的形成过程中起重要作用;（2）肝复康对肝纤维化有疗效,其作用机制可能与降低肝组织JAK2和STAT3的表达,阻断JAK2/STAT3信号通路有关。     

STAT3与甲状腺癌

信号转导与转录激活因子(STAT)3是STATs家族的重要成员之一,能影响一系列基因的转录和表达,在细胞增殖、分化、衰老和凋亡中发挥重要作用.研究发现,在多种人类肿瘤细胞中均有STAT3持续性激活诱导的相应蛋白高表达,这些蛋白可以促进肿瘤发生、发展、侵袭和转移,并抑制肿瘤细胞凋亡.活化的STAT3与甲状腺癌的发生、发展及恶性生物学行为密切相关,有望成为甲状腺癌治疗的新靶标.     

转化生长因子β1介导的心肌肥厚发生机制研究进展

转化生长因子β是迄今为止已知的最为有效且功能较多的多肽类物质之一。由多种细胞以自分泌、旁分泌和内分泌的方式通过多种受体信号转导通路促进蛋白质的合成,参与调节胚胎发育、细胞生长和分化、细胞增殖与凋亡、胞外基质合成、炎症、创伤修复及免疫反应等许多生物学过程。它分成多个亚型,其中转化生长因子β1促进心肌细胞外基质合成与沉积,是最重要的促心肌纤维化细胞因子,并与多种激素、细胞因子相互作用,促进心肌肥厚的发生发展,本文就此作一综述。     

转化生长因子β在支气管哮喘气道平滑肌重塑中的作用

支气管哮喘(简称哮喘)是一种气道慢性炎症,持续的气道炎症导致气道重塑、不完全可逆的气流受限和进行性的肺功能受损.平滑肌细胞的增殖(包括增生和肥大)是哮喘气道重塑的特征性改变,是哮喘气道反应性和严重程度相关的重要因素之一.转化生长因子β(TGF-β)能够诱导分化、炎症、增生以及凋亡等多种细胞反应,促进平滑肌细胞的增生、肥大和迁移,在气道重塑中发挥重要作用.减少TGF-β的产生以及控制TGF-β的效应有利于对慢性哮喘气道重塑的干预治疗.     

生存素与肿瘤信号转导通路之间的关系

生存素是凋亡抑制蛋白家族新成员,是细胞增殖和凋亡调控界面间的结点分子.生存素基因表达的肿瘤特异性使其成为目前恶性肿瘤诊断和治疗的新靶点.肿瘤细胞发生与正常细胞的信号通路异常有关,信号转导通路的活化参与细胞癌变、增殖、凋亡等多种生物学效应.本文就肿瘤中信号转导对生存素基因的表达调控机制的研究进展作一综述.