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Ethanol-induced cerebellar hypoplasia is associated with inhibition of insulin-stimulated survival signaling. The present work explores the mechanisms of impaired insulin signaling in a rat model of fetal alcohol syndrome. Real-time quantitative RT-PCR demonstrated reduced expression of the insulin gene in cerebella of ethanol-exposed pups. Although receptor expression was unaffected, insulin and insulin-like growth factor (IGF-I) receptor tyrosine kinase (RTK) activities were reduced by ethanol exposure, and these abnormalities were associated with increased PTP1b activity. In addition, glucose transporter molecule expression and steady-state levels of ATP were reduced in ethanol-exposed cerebellar tissue. Cultured cerebellar granule neurons from ethanol-exposed pups had reduced expression of genes encoding insulin, IGF-II, and the IGF-I and IGF-II receptors, and impaired insulin- and IGF-I-stimulated glucose uptake and ATP production. The results demonstrate that ethanol inhibits insulin-mediated actions in the developing brain by reducing local insulin production and insulin RTK activation, leading to inhibition of glucose transport and ATP production.Received 30 December 2004; received after revision 1 March 2005; accepted 10 March 2005 相似文献
3.
Bitter peptides and bitter taste receptors 总被引:1,自引:0,他引:1
Bitter peptides are a structurally diverse group of oligopeptides often generated in fermented, aged, and hydrolyzed food
products that make them unfavorable for consumption. Humans perceive bitterness by a repertoire of 25 human bitter receptors,
termed T2Rs. Knowledge of the structural features of bitter receptors and of the factors that stimulate bitter receptors will
aid in understanding the mechanism responsible for bitter taste perception. This article reviews the current knowledge regarding
structural features of bitter peptides and bitter taste receptors.
Received 24 November 2008; received after revision 11 December 2008; accepted 16 December 2008 相似文献
4.
Regulation of insulin receptor function 总被引:1,自引:0,他引:1
Youngren JF 《Cellular and molecular life sciences : CMLS》2007,64(7-8):873-891
Resistance to the biological actions of insulin contributes to the development of type 2 diabetes and risk of cardiovascular
disease. A reduced biological response to insulin by tissues results from an impairment in the cascade of phosphorylation
events within cells that regulate the activity of enzymes comprising the insulin signaling pathway. In most models of insulin
resistance, there is evidence that this decrement in insulin signaling begins with either the activation or substrate kinase
activity of the insulin receptor (IR), which is the only component of the pathway that is unique to insulin action. Activation
of the IR can be impaired by post-translational modifications of the protein involving serine phosphorylation, or by binding
to inhibiting proteins such as PC-1 or members of the SOCS or Grb protein families. The impact of these processes on the conformational
changes and phosphorylation events required for full signaling activity, as well as the role of these mechanisms in human
disease, is reviewed in this article.
Received 3 August 2006; received after revision 1 December 2006; accepted 8 January 2007 相似文献
5.
Lanzi C Cassinelli G Cuccuru G Zaffaroni N Supino R Vignati S Zanchi C Yamamoto M Zunino F 《Cellular and molecular life sciences : CMLS》2003,60(7):1449-1459
Genetic alterations causing oncogenic activation of the RET gene are recognized as pathogenic
events in papillary and medullary thyroid carcinomas. Inhibition of Ret oncoprotein functions could
thereby represent a specific therapeutic approach. We previously described the inhibitory activity
of the 2-indolinone derivative RPI-1 (formerly Cpd1) on the tyrosine kinase activity and transforming
ability of the products of the RET/PTC1 oncogene exogenously expressed in murine cells. In the
present study, we investigated the effects of RPI-1 in the human papillary thyroid carcinoma cell
line TPC-1 spontaneously harboring the RET/PTC1 rearrangement. Treatment with RPI-1 inhibited cell
proliferation and induced accumulation of cells at the G2 cell cycle phase. In treated cells,
Ret/Ptc1 tyrosine phosphorylation was abolished along with its binding to Shc and phospholipase
C, thereby indicating abrogation of constitutive signaling mediated by the oncoprotein. Activation
of JNK2 and AKT was abolished, thus supporting the drug inhibitory efficacy on downstream pathways.
In addition, cell growth inhibition was associated with a reduction in telomerase activity by nearly
85%. These findings in a cellular context relevant to the pathological function of RET oncogenes
support the role of Ret oncoproteins as useful targets for therapeutic intervention, and suggest
RPI-1 as a promising candidate for preclinical development in the treatment of thyroid tumors
expressing RET oncogenes.Received 31 December 2002; received after revision 21 February 2003; accepted 10 April 2003 相似文献
6.
Signal regulation by family conspiracy 总被引:6,自引:0,他引:6
The signal regulating proteins (SIRPs) are a family of ubiquitously expressed transmembrane glycoproteins composed of two
subgroups: SIRPα and SIRPβ, containing more than ten members. SIRPα has been shown to inhibit signalling through a variety of receptors including receptor tyrosine kinases and cytokine receptors.
This function involves protein tyrosine kinases and is dependent on immunoreceptor tyrosine-based inhibition motifs which
recruit key protein tyrosine phosphatases to the membrane. Negative regulation by SIRPα may also involve its ligand, CD47, in a bi-directional signalling mechanism. The SIRPβ subtype has no cytoplasmic domain but instead associates with at least one other transmembrane protein (DAP-12, or KARAP).
DAP-12 possesses immunoreceptor tyrosine-based activation motifs within its cytoplasmic domain that are thought to link SIRPβ to activating machinery. SIRPα and SIRPβ thus have complementary roles in signal regulation and may conspire to tune the response to a stimulus.
Received 6 July 2000; revised 2 August 2000; accepted 5 August 2000 相似文献
7.
The role of VEGF receptors in angiogenesis; complex partnerships 总被引:6,自引:0,他引:6
Cébe-Suarez S Zehnder-Fjällman A Ballmer-Hofer K 《Cellular and molecular life sciences : CMLS》2006,63(5):601-615
Vascular endothelial growth factors (VEGFs) regulate blood and lymphatic vessel development and homeostasis but also have
profound effects on neural cells. VEGFs are predominantly produced by endothelial, hematopoietic and stromal cells in response
to hypoxia and upon stimulation with growth factors such as transforming growth factors, interleukins or platelet-derived
growth factor. VEGFs bind to three variants of type III receptor tyrosine kinases, VEGF receptor 1, 2 and 3. Each VEGF isoform
binds to a particular subset of these receptors giving rise to the formation of receptor homo- and heterodimers that activate
discrete signaling pathways. Signal specificity of VEGF receptors is further modulated upon recruitment of coreceptors, such
as neuropilins, heparan sulfate, integrins or cadherins. Here we summarize the knowledge accumulated since the discovery of
these proteins more than 20 years ago with the emphasis on the signaling pathways activated by VEGF receptors in endothelial
cells during cell migration, growth and differentiation.
Received 15 September 2005; received after revision 11 November; accepted 24 November 2005 相似文献
8.
The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in regulating cell proliferation, survival, differentiation and migration. The ErbB receptors carry out both redundant and restricted functions in mammalian development and in the maintenance of tissues in the adult mammal. Loss of regulation of the ErbB receptors underlies many human diseases, most notably cancer. Our understanding of the function and complex regulation of these receptors has fueled the development of targeted therapeutic agents for human malignancies in the last 15 years. Here we review the biology of ErbB receptors, including their structure, signaling, regulation, and roles in development and disease, then briefly touch on their increasing roles as targets for cancer therapy. 相似文献
9.
Nicotinic acetylcholine receptors (nAChRs) exist in many subtypes and are found in the peripheral and central nervous system
where they mediate or modulate synaptic transmission. We review how tyrosine phosphorylation and kinases regulate muscle and
neuronal nAChRs. Interestingly, although some of the same kinase players interact with the various receptor subtypes, the
functional consequences are different. While concerted action of MuSK, Abl- and Src-family kinases (SFKs) regulates the synaptic
distribution of nAChRs at the neuromuscular junction, SFKs activate heteromeric neuronal nAChRs in adrenal chromaffin cells,
thereby enhancing catecholamine secretion. In contrast, the activity of homomeric neuronal nAChRs, as found in the hippocampus,
is negatively regulated by tyrosine phosphorylation and SFKs. It appears that tyrosine kinases provide the means to regulate
all nAChRs; but the functional consequences, even those caused by the same kinase family, are specific for each receptor subtype
and location.
Received 21 February 2006; received after revision 24 July 2006; accepted 30 August 2006 相似文献
10.
Regulation of neutrophil apoptosis via death receptors 总被引:4,自引:0,他引:4