Protein tyrosine phosphatases play an essential role in the control of leucocyte cell growth an differentiation. Recently a new receptor type membrane tyrosine phosphatase named CD148 has been identified. This molecule is present on the membrane of all the hematopoietic lineages as well as on several other cell types, mainly epithelial cells and its expression increases after cell activation. This molecule is able to act as a transducing molecule. Moreover, CD148 is able to modulate the signal transduction through the TCR/CD3 complex, in a manner similar to CD45. It has also been suggested that CD148 could be involved in mechanisms of differentiation and inhibition of cell growth. In addition, CD148 seems to be associated with a serine/threonine kinase in certain epitelial cell lines and leucocytes. Here, we review recent data on the expression and function of CD148 in both human, mouse and rat. 相似文献
Sensitization of nociceptive dorsal horn neurons, including spinothalamic tract (STT) cells, is thought to underlie the development of secondary hyperalgesia and allodynia following tissue injury. In central sensitization, responses to stimulation of sensory receptors are enhanced without any change in the excitability of the primary afferent neurons. We hypothesize that central sensitization of STT neurons is a variety of long-term potentiation (LTP). Evidence that LTP occurs in the spinal cord is reviewed. Neurotransmitters that trigger central sensitization include excitatory amino acids and peptides. Evidence for this is that co-activation of N-methyl-
-aspartate and NK1 receptors can produce long-lasting increases in the responses of STT cells, and antagonists of these receptors prevent central sensitization. Responses to excitatory amino acids increase and those to inhibitory amino acids decrease during central sensitization, presumably accounting for the changed excitability of STT cells. We believe these changes result from the activation of signal transduction pathways, including the protein kinase C, NO/protein kinase G and protein kinase A cascades. Recent evidence shows that calcium/calmodulin dependent kinase II (CaMKII) is also upregulated early in the process of central sensitization and that several types of ionotropic glutamate receptors become phosphorylated. It is proposed that the phosphorylation of neurotransmitter receptors leads to alterations in the sensitivity of these receptors and to central sensitization. Comparable events occur during LTP in brain structures. 相似文献
Background Angiotensin II (Ang II) acting at angiotensin AT1 receptor (AT1R) has well documented effects on cardiovascular structure such as the promotion of cardiovascular hypertrophy and fibrosis, which are believed to be opposed by angiotensin AT2 receptor (AT2R) stimulation. The expressions of AT1R and AT2R are up-regulated in senescent hearts. The purpose of this study was to investigate the interaction of signal transduction between AT1R and AT2R, and to detect whether there is any difference in the interaction in rat hearts of different age. Methods In 3.5-, 12-, 18- and 24-month-old rats, the heart cell membrane activities of protein kinase C (PKC) and tyrosine kinase were measured when AT1R and AT2R were both activated by Ang II or just the AT1R was activated by Ang II and PD123319. The activities of cytosolic phospholipase A2 (cPLA2) and the levels of cGMP were investigated when AT1R and AT2R were both activated by Ang II or just the AT2R was activated by Ang II and losartan. Results When AT1R and AT2R were both activated compared to when the AT1R was activated, the activities of PKC were not different in hearts from 3.5- and 12-month-old rats, but decreased significantly in 18- and 24-month-old rats; the activities of tyrosine kinase were not different in 3.5-month-old rats but decreased significantly in 12-, 18- and 24-month-old rats. The activities of cPLA2 were all decreased significantly in rats of different age when AT1R and AT2R were both activated compared to when the AT2R was activated. Treatment with Ang II alone compared to Ang II and losartan decreased the levels of cGMP (fmol/mg) in rats of different age (102.7±12.7 versus 86.0±8.0 in 3.5-month-old rats, P<0.05; 81.0±9.4 versus 70.0±6.3 in 12-month-old rats, P<0.05; 69.8±5.6 versus 54.2±5.3 in 18-month-old rats, P<0.01; 57.7±8.0 versus 39.0±3.0 in 24-month-old rats, P<0.01). Conclusions The activation of AT1R inhibited the signal transduction of AT2R during the aging variation, and the activation of AT2R inhibited the signal transduction of AT1R in rat heart of different age.
Background T cell immune abnormalities in patients with dilated cardiomyopathy (DCM) has been intensively studied over the past 10 years. Our previous study has suggested that immunization of mice with the peptides derived from human adenine nucleotide translocator (ANT) result in the production of autoantibodies against the ANT and histopathological changes similar to those in human DCM. The ANT peptides can induce autoimmune cardiomyopathy like DCM in Balb/c mice. In this study we aimed to focus on the molecular mechanism of T cells in the autoimmune cardiomyopathy mouse model by detecting the expression of the two T cell signaling molecules.Methods The ANT peptides were used to cause autoimmune cardiomyopathy in Balb/c mice. Anti-L3T4 or rat anti-mouse IgG was administered to the mice (n=6 in each group) simultaneously immunized with ANT. ELISA analysis was used to detect autoantibodies against the ANT peptides and the percentages of interferon-γ and interleukin-4 producing cells among splenic CD4(+) lymphocytes was determined by using flow cytometry analysis. The expression of CD45 in spleen T cells was determined by immunohistochemistry and the mRNAs of T cell signaling molecules were detected by real-time PCR.Results Treatment of ANT immunized Balb/c mice with anti-CD4 mAb caused a reduction in the gene expression of P56lck and Zap-70 and a lower level of CD45 expression by spleen T cells. Also, a reverse of the Th1/Th2 ratio that results in the reduced production of antibodies against ANT was found in the anti-CD4 monoclonal antibodies (mAb) group. Whereas irrelevant antibody (rat anti-mouse IgG) did not suppress T cell signaling molecules nor inhibit CD45 expression, and control-antibody mice did not show any significant differences compared with the DCM group.Conclusion The results show that anti-CD4 mAb is a powerful inhibitor of the early initiating events of T cell receptor (TCR) signal transduction in mouse autoimmune dilated cardiomyopathy. 相似文献
The rearranged during transfection (RET) proto-oncogene encodes a receptor tyrosine kinase that is implicated in the development of endocrine tumors of the thyroid
and adrenal glands. In humans, activating RET mutations are found in the inherited cancer syndrome multiple endocrine neoplasia 2 and in sporadic medullary and papillary
thyroid carcinomas. The specific type and location of RET mutations are strongly correlated with the disease phenotype and
have both diagnostic and prognostic value. Recent advances in the molecular characterization of the RET receptor and its mutants
have begun to define the mechanisms underlying the transforming ability of the different RET mutant forms. This information
has revealed key functional features of these mutant proteins that distinguish the different clinically recognized mutations
and provide clues as to the functional origins of the phenotypes associated with specific RET mutations. The elucidation of
molecular mechanisms involved in RET-mediated transformation is a key step in the development of much needed therapeutics
that target RET’s oncogenic properties. Recent advances have begun to provide a deeper understanding of the receptor’s function,
and dysfunction, in human tumors that may guide this process. 相似文献
Malignant melanoma originates in melanocytes, the pigment-producing cells of the skin and eye, and is one of the most deadly human cancers with no effective cure for metastatic disease. Like many other cancers, melanoma has both environmental and genetic components. For more than 20 years, the melanoma genome has been subject to extensive scrutiny, which has led to the identification of several genes that contribute to melanoma genesis and progression. Three molecular pathways have been found to be nearly invariably dysregulated in melanocytic tumors, including the RAS-RAF-MEK-ERK pathway (through mutation of BRAF, NRAS or KIT), the p16 INK4A-CDK4-RB pathway (through mutation of INK4A or CDK4) and the ARF-p53 pathway (through mutation of ARF or TP53). Less frequently targeted pathways include the PI3K-AKT pathway (through mutation of NRAS, PTEN or PIK3CA) and the canonical Wnt signaling pathway (through mutation of CTNNB1 or APC). Beyond the specific and well-characterized genetic events leading to activation of proto-oncogenes or inactivation of tumor suppressor genes in these pathways, systematic high-resolution genomic analysis of melanoma specimens has revealed recurrent DNA copy number aberrations as well as perturbations of DNA methylation patterns. Melanoma provides one of the best examples of how genomic analysis can lead to a better understanding of tumor biology. We review current knowledge of the genes involved in the development of melanoma and the molecular pathways in which these genes operate. 相似文献
Interaction of the TCR complex with self- or foreign peptides is a central event in the immune responses. Upon TCR stimulation, a protein-tyrosine kinase (PTK), ZAP-70, is recruited to signaling units of the TCR complex, such as TCRzeta, to play an essential role in T cell activation. Here, we find that mice lacking adaptor proteins Dok-1 and Dok-2 show augmented responses to thymus-dependent, but not thymus-independent, antigens, and that their T cells show elevated responses to TCR stimulation, including the activation of ZAP-70 and subsequent proliferation and cytokine production. Furthermore, the forced expression of Dok-1 or Dok-2 in a CD3(+)CD4(+) T cell clone inhibited the activation of ZAP-70 upon TCR stimulation. Interestingly, the Dok-1 and Dok-2 COOH-terminal moieties bearing the src homology 2 target motifs were dispensable for this negative regulation, even though they are crucial for the known adaptor function of Dok-family proteins. Thus, by an as yet unidentified mechanism, Dok-1 and Dok-2 play an essential role in the negative regulation of TCR signaling. Consistently, all mice lacking these proteins exhibited elevated titers of antibodies to double-stranded DNA and developed lupus-like renal disease. 相似文献