The processes of T-cell development and activation employ similar immature and mature receptors as well as similar signal transduction pathways to achieve different outcomes. Many signaling molecules are shared between the receptor signaling pathways, including two families of cytoplasmic protein tyrosine kinases, the Src family and the Syk family. The two Syk family members expressed in T cells, Syk and ZAP-70, are structurally similar but are expressed at different times during thymic development and during T-cell activation. These two kinases, although they share many physical features, differ in terms of biochemical activity and regulation. We discuss the overlapping and distinct characteristics of Syk and ZAP-70 in T-cell signaling and the potential biological importance of their differences.
The protein tyrosine phosphatase CD45 is a critical component of the T cell antigen receptor (TCR) signaling pathway, acting as a positive regulator of Src family protein tyrosine kinases (PTKs) such as Lck. Most CD45‐deficient human and murine T cell lines are unable to signal through their TCRs. However, there is a CD45‐deficient cell line that can signal through its TCR. We have studied this cell line to identify a TCR signaling pathway that is independent of CD45 regulation. In the course of these experiments, we found that the Syk PTK, but not the ZAP‐70 PTK, is able to mediate TCR signaling independently of CD45 and of Lck. For this function, Syk requires functional kinase and SH2 domains, as well as intact phosphorylation sites in the regulatory loop of its kinase domain. Thus, differential expression of Syk is likely to explain the paradoxical phenotypes of different CD45‐deficient T cells. Finally, these results suggest differences in activation requirements between two closely related PTK family members, Syk and ZAP‐70. The differential activities of these two kinases suggest that they may play distinct, rather than completely redundant, roles in lymphocyte signaling.
AP-2 transcription factors have been implicated in epidermal biology, but their functional significance has remained elusive. Using conditional knockout technology, we show that AP-2α is essential for governing the balance between growth and differentiation in epidermis. In vivo, epidermis lacking AP-2α exhibits elevated expression of the epidermal growth factor receptor (EGFR) in the differentiating layers, resulting in hyperproliferation when the receptors are activated. Chromatin immunoprecipitation and promoter activity assays identify EGFR as a direct target gene for AP-2α repression, and, in the absence of AP-2α, this is manifested primarily in excessive EGF-dependent phosphoinositol-3 kinase/Akt activity. Together, our findings unveil a hitherto unrecognized repressive role for AP-2α in governing EGFR gene transcription as cells exit the basal layer and withdraw from the cell cycle. These results provide insights into why elevated AP-2α levels are often associated with terminal differentiation and why tumor cells often display reduced AP-2α and elevated EGFR proteins.
Purpose-To compare visual field defects obtained with both multifocal visual evoked potential (mfVEP) and Humphrey visual field (HVF) techniques to topographic optic disc measurements in patients with normal tension glaucoma (NTG) and high tension glaucoma (HTG).Methods-We studied 32 patients with NTG and 32 with HTG. All patients had reliable 24-2 HVFs with a mean deviation (MD) of −10 dB or better, a glaucomatous optic disc and an abnormal HVF in at least one eye. Multifocal VEPs were obtained from each eye and probability plots created. The mfVEP and HVF probability plots were divided into a central 10-degree (radius) and an outer arcuate subfield in both superior and inferior hemifields. Cluster analyses and counts of abnormal points were performed in each subfield. Optic disc images were obtained with the Heidelberg Retina Tomograph III (HRT III). Eleven stereometric parameters were calculated. Moorfields regression analysis (MRA) and the glaucoma probability score (GPS) were performed.Results-There were no significant differences in MD and PSD values between NTG and HTG eyes. However, NTG eyes had a higher percentage of abnormal test points and clusters of abnormal points in the central subfields on both mfVEP and HVF than HTG eyes. For HRT III, there were no significant differences in the 11 stereometric parameters or in the MRA and GPS analyses of the optic disc images.Conclusions-The visual field data suggest more localized and central defects for NTG than HTG.
. Heat shock-mediated thermoprotection of larval locomotion compromised by ubiquitous overexpression of Hsp70 in Drosophila melanogaster. J Neurophysiol 94: 3563-3572, 2005. First published August 10, 2005 doi:10.1152/jn.00723.2005. Maintaining the competence of locomotor circuitry under stressful conditions can benefit organisms by enabling locomotion to more tolerable microhabitats. We show that prior heat shock protects locomotion and the locomotor central pattern generator of larval Drosophila against subsequent hyperthermic stress. We combined molecular genetic, electrophysiological, and behavioral techniques to investigate heat shock-mediated thermoprotection. Prior heat shock increased the distance traveled by larvae during hyperthermia before failure. The frequency of the rhythm of peristaltic locomotor contractions and the velocity of locomotion were both less thermosensitive after heat shock and were less susceptible to failure at high temperatures. Rhythmic coordinated motor patterns, recorded intracellularly as excitatory junction potentials in body wall muscles of dissected preparations, were centrally generated because patterns could still be generated in the absence of sensory feedback (sensory function disrupted with shibire). Prior heat shock protected central circuit operation during hyperthermic stress by increasing the temperature at which it failed. Overexpression of Hsp70 after a heat shock using transgenic flies (traII) did not enhance thermoprotection, as expected, but had deleterious effects on parameters of behavior.
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