Regulation of G protein-mediated signal transduction by RGS proteins

RGS proteins form a new family of regulatory proteins of G protein signaling. They contain homologous core domains (RGS domains) of about 120 amino acids. RGS domains interact with activated Galpha subunits. Several RGS proteins have been shown biochemically to act as GTPase activating proteins (GAPs) for their interacting Galpha subunits. Other than RGS domains, RGS proteins differ significantly in size, amino acid sequences, and tissue distribution. In addition, many RGS proteins have other protein-protein interaction motifs involved in cell signaling. We have shown that p115RhoGEF, a newly identified GEF(guanine nucleotide exchange factor) for RhoGTPase, has a RGS domain at its N-terminal region and this domain acts as a specific GAP for Galpha12 and Galpha13. Furthermore, binding of activated Galpha13 to this RGS domain stimulated GEF activity of p115RhoGEF. Activated Galpha12 inhibited Galpha13-stimulated GEF activity. Thus p115RhoGEF is a direct link between heterotrimeric G protein and RhoGTPase and it functions as an effector for Galpha12 and Galpha13 in addition to acting as their GAP. We also found that RGS domain at N-terminal regions of G protein receptor kinase 2 (GRK2) specifically interacts with Galphaq/11 and inhibits Galphaq-mediated activation of PLC-beta, apparently through sequestration of activated Galphaq. However, unlike other RGS proteins, this RGS domain did not show significant GAP activity to Galphaq. These results indicate that RGS proteins have far more diverse functions than acting simply as GAPs and the characterization of function of each RGS protein is crucial to understand the G protein signaling network in cells.     

Regulation of apoptotic signal transduction pathways by the heat shock proteins

The study about apoptotic signal transductions has become a project to reveal the molecular mechanisms of apoptosis. Heat shock proteins (hsps), which play an important role in cell growth and apoptosis, have attracted great attentions. A lot of researches have showed there is a hsps superfamily including hsp90, hsp70, hsp60 and hsp27, etc., which regulates the biological behaviors of cells, particularly apoptotic signal transduction in Fas pathway, JNK/SAPK pathway and caspases pathway at different levels, partly by the function of molecular chaperone.     

MAPK信号转导通路对炎证反应的调控

丝裂原活化蛋白激酶（ｍｉｔｏｈｅｎ－ａｃｔｅｖａｔｃｄ ｐｒｏｔｅｉｎ ｋｉｎａｓａ,ＭＡＰＫ）是生物体内重要的信号转导系统之一,参与介导生长、发育、化裂、分化、死亡以及细胞间的功能同步等多种细胞过程,在哺乳动物细胞中已发现和克隆了ＥＲＫ、ＪＮＫ／ＳＡＰＫ、ｐ３８／ＲＫ、ＥＲＫ５／ＢＭＫ１四个ＭＡＰＫ亚族。这些ＭＡＰＫ能被多种炎性刺激所激活,并对炎症的发生、发展起生重要调控作用。研究感染和炎症反应     

Regulation of ROS signal transduction by NADPH oxidase 4 localization

Reactive oxygen species (ROS) function as intracellular signaling molecules in a diverse range of biological processes. However, it is unclear how freely diffusible ROS dictate specific cellular responses. In this study, we demonstrate that nicotinamide adenine dinucleotide phosphate reduced oxidase 4 (Nox4), a major Nox isoform expressed in nonphagocytic cells, including vascular endothelium, is localized to the endoplasmic reticulum (ER). ER localization of Nox4 is critical for the regulation of protein tyrosine phosphatase (PTP) 1B, also an ER resident, through redox-mediated signaling. Nox4-mediated oxidation and inactivation of PTP1B in the ER serves as a regulatory switch for epidermal growth factor (EGF) receptor trafficking and specifically acts to terminate EGF signaling. Consistent with this notion, PTP1B oxidation could also be modulated by ER targeting of antioxidant enzymes but not their untargeted counterparts. These data indicate that the specificity of intracellular ROS-mediated signal transduction may be modulated by the localization of Nox isoforms within specific subcellular compartments.     

AGS3蛋白与G蛋白信号转导

AGS3蛋白是影响受体到G蛋白的信号转导或直接影响非受体依赖型G蛋白激活的蛋白质之一。AGS3蛋白在脑、睾丸、肝脏、肾脏、心脏、胰腺及PC-12细胞中普遍分布。它不仅具有不依赖受体的Gβγ信号转导激活物的作用,也能作为二磷酸乌苷（GDP）的解离抑制剂,并负向调节G蛋白偶联受体对G蛋白的激活。AGSl、AGS2、AGS4是AGS家族的其它几个成员,能选择性激活不同类型的G蛋白。LGN和PINS蛋白是AGS3的同系物。AGS3蛋白与信号转导的关系是目前研究的热点之一。     

Intermediate filament proteins participate in signal transduction

How timely transport of chemical signals between the distal end of long axonal processes and the cell bodies of neurons occurs is an interesting and unresolved issue. Recently, Perlson et al. presented evidence that cleavage products of newly synthesized vimentin, an intermediate filament (IF) protein, interact with mitogen-activated protein (MAP) kinases at sites of axon injury. These IF fragments appear to be required for the transport of these kinases to the cell body along microtubule tracks. The truncated vimentin is instrumental in signal propagation as it provides a scaffold that brings together activated MAP kinases (such as Erk 1 and Erk2), as well as importin beta and cytoplasmic dynein. The authors propose that this all-in-one transport complex has the extraordinary ability to travel towards the cell body and enter the nucleus where the kinases activate and influence gene expression so that a neuron can generate a timely response to injury.     

Ras proteins and theras-related signal transduction pathway

Summary Mammalianras genes may naturally acquire oncogenic transformation potential through some point mutations which result in the impairment of the normalras protein functions, and which are localised in codons 12, 13 or 61. Mutationally activatedras alleles were found in a wide variety of human and carcinogen (including radiation)-induced animal malignancies. In man, myeloid leukemias are often associated with the presence of a mutationally activatedras gene (for review, see Bos JL (1989), Cancer Res 49:4682–4689). However, we failed till now in our attempts to detect oncogenicras mutations in radiation-induced mouse myeloid leukemias. We thus have the feeling thatras might perhaps participate to tumorigenesis through another mechanism provoking a deregulation of theras protein functions. In order to help evaluate such a possibility, we give here a very concise overview of the properties of theras proteins and of their regulation by a variety of still hypothetical molecular switches. This overview does not include bibliographic references. Indeed, we gathered much of the information described below at the Cold Spring Harbor Symposium on Function and Evolution ofras Proteins, May 9–13, 1990. Communications presented at Cold Spring Harbor Symposia may contain preliminary data and should not be cited in bibliographies. Another voluntary omission in this overview is that, for the sake of simplicity, we do not mention whether the data were obtained from experiments performed on H-, K- or N-ras. Details can be found in the published book of abstracts.     

Distinct involvement of the Gab1 and Grb2 adaptor proteins in signal transduction by the related receptor tyrosine kinases RON and MET

Although the signal transduction mechanisms of the receptor tyrosine kinase MET are well defined, less is known about its close relative RON. MET initiates intracellular signaling by autophosphorylation on specific cytoplasmic tyrosines that form docking sites for the adaptor proteins Grb2 and Gab1. Grb2 binds directly and is essential for all of the biological activities of MET. Gab1 docks either directly or indirectly via Grb2 and controls only a subset of MET functions. Because MET and RON possess similar adaptor binding sites, it was anticipated that their adaptor interactions would be conserved. Here we show that in contrast to MET, RON relies primarily on Gab1 for signal transmission. Surprisingly, disruption of the Grb2 docking site of RON or Grb2 depletion augments activity, whereas enhancement of Grb2 binding attenuates Gab1 recruitment and signaling. Hence, RON and MET differ in their adaptor interactions; furthermore, Grb2 performs a novel antagonistic role in the context of RON signaling.     

学习记忆相关信号转导蛋白

近年来,国内外大量研究从信号转导角度探讨衰老性学习记忆减退分子机制,为延缓老年性记忆退化和治疗老年性疾病提供新的思路。本文主要从学习记忆相关信号转导蛋白角度,综述近年来国内外相关研究进展,结合我们课题组的研究思路和方向,就进一步的研究提出展望。