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The level of tyrosine phosphorylation of cellular glycoproteins isolated by wheat germ agglutinin chromatography in cells infected with a variety of kinase-positive/transformation-defective src mutants was examined in an effort to identify cellular membrane proteins whose phosphorylation correlates with phenotypic transformation. We have identified two glycoproteins, with molecular masses of 95 and 135 kilodaltons, whose phosphorylation correlates with morphological transformation, growth in soft agar, and an increase in the rate of 2-deoxyglucose uptake. The strong correlation obtained between transformation and phosphorylation of these proteins suggests that they may be substrates for pp60src which are important in the process of transformation.
Phospholipase C-gamma 1 (PLC-gamma 1) is a substrate for several receptor tyrosine kinases and its catalytic activity is increased by tyrosine phosphorylation. However, the biological significance of this molecule in normal or malignant human epithelial cell proliferation is unknown. We determined the relative content of PLC-gamma 1 in primary human mammary carcinomas and in nonmalignant mammary tissues. By Western blot and immunohistochemistry, considerably higher levels of PLC-gamma 1 protein were detectable in the majority of carcinomas and in one of two benign fibroadenomas compared to normal breast tissues. In 18 of 21 carcinomas that contained high levels of PLC-gamma 1, the presence of phosphotyrosine on PLC-gamma 1 could also be detected. All carcinomas in which tyrosine phosphorylated PLC-gamma 1 was present also expressed detectable levels of the epidermal growth factor receptor or erbB-2, two tyrosine kinases known to phosphorylate this enzyme. Thus, a high percentage of mammary carcinomas concomitantly display increased levels of receptor tyrosine kinases and a direct tyrosine phosphorylation substrate, thereby potentially amplifying two successive steps in a signal transduction pathway.
Dopamine beta-hydroxylase (DBH) deficiency is a genetic disorder in which affected patients cannot synthesize norepinephrine, epinephrine, and octopamine in either the central nervous system or the peripheral autonomic neurons. Dopamine acts as a false neurotransmitter in their noradrenergic neurons. Neonates with DBH deficiency have had episodic hypothermia, hypoglycemia, and hypotension, but survivors sometimes cope relatively well until late childhood when overwhelming orthostatic hypotension profoundly limits their activities. The hypotension may be so severe that clonic seizures supervene. Most currently recognized patients are young or middle-aged adults. The diagnosis is established by the observation of severe orthostatic hypotension in a patient whose plasma norepinephrine/dopamine ratio is much less than one.
Ltk is a new member of the ros/insulin receptor family of tyrosine kinases that is expressed in murine B-lymphocyte precursors and forebrain neurons. We previously reported that lymphoid ltk cDNAs predict a 69 kDa transmembrane glycoprotein, which uses a CUG translational start codon and has a 110 amino acid putative extracellular domain. We now show that the predominant ltk mRNA in brain is alternatively spliced and predicts a protein with a substantially larger extracellular part. The human ltk gene maps to chromosome 15, bands q13-21, a region containing the breakpoint of a recurring chromosomal abnormality in B-cell non-Hodgkin lymphomas.
Expression of the Rous sarcoma virus-encoded oncoprotein, pp60v-src, subverts the normal regulation of cell growth, which results in oncogenic transformation. This process requires the intrinsic protein-tyrosine kinase activity of pp60v-src and is associated with an increase in tyrosine phosphorylation of a number of cellular proteins, candidate substrates for pp60v-src. We report here the isolation of a cDNA encoding a protein, pp125, that is a major phosphotyrosine-containing protein in untransformed chicken embryo cells and exhibits an increase in phosphotyrosine in pp60v-src-transformed chicken embryo cells. This cDNA encodes a cytoplasmic protein-tyrosine kinase which, based upon its predicted amino acid sequence and structure, is the prototype for an additional family of protein-tyrosine kinases. Immunofluorescence localization experiments show that pp125 is localized to focal adhesions; hence, we suggest the name focal adhesion kinase.
We have used transient expression assays to identify a cis-acting region in the 5' flanking sequence of murine c-mos which, when deleted, allows expression from the c-mos promoter in NIH 3T3 cells. This negative regulatory sequence, located 400 to 500 nucleotides upstream of the c-mos ATG, also inhibited expression from a heterologous promoter. In addition to NIH 3T3 cells, the c-mos negative regulatory sequence was active in BALB/3T3 cells, PC12 rat pheochromocytoma cells, and A549 human lung carcinoma cells. Site-specific mutagenesis identified three possibly interacting regions that were involved in negative regulatory activity, located around -460, -425, and -405 with respect to the ATG. RNase protection analysis indicated that once the negative regulatory sequences were deleted, transcription in NIH 3T3 cells initiated from the same transcription initiation sites normally utilized in spermatocytes, approximately 280 nucleotides upstream of the ATG. Deletions beyond the spermatocyte promoter, however, allowed transcription initiation from progressively downstream c-mos sequences. Deletion or mutation of sequences surrounding the oocyte promoter at -53 also had little effect on expression of c-mos constructs in NIH 3T3 cells. Therefore, the major determinant of c-mos expression in NIH 3T3 cells was removal of the negative regulatory sequence rather than the utilization of a unique promoter. The c-mos negative regulatory sequences thus appear to play a significant role in tissue-specific c-mos expression by inhibiting transcription in somatic cells.
The effects of prefrontal cortical dopamine depletion on subcortical dopamine function in the rat were examined. 6-Hydroxydopamine lesions of the dopaminergic innervation of the prefrontal cortex did not alter concentrations of dopamine or its metabolite 3,4-dihydroxyphenylacetic acid in either the striatum or nucleus accumbens. Similarly, the activity of the catecholamine biosynthetic enzyme tyrosine hydroxylase in the striatal complex was not changed in animals with prefrontal cortical lesions. Animals sustaining neurotoxic lesions of the prefrontal cortex were challenged with haloperidol in order to activate submaximally tyrosine hydroxylase activity. The magnitude of the haloperidol-induced increase in enzyme activity in the nucleus accumbens was significantly greater in lesioned subjects than in control animals. These data suggest that lesions of the prefrontal cortical dopamine innervation do not result in significant alterations in basal dopaminergic function in the striatal complex. However, lesions of the dopaminergic innervation of the prefrontal cortex significantly increase the responsiveness of mesolimbic dopamine afferents to pharmacological challenge.
Recent anatomical data suggest that the nucleus accumbens can be parcellated into a core region, related to the caudate-putamen, and a shell region, associated with the limbic system. We have used pharmacological methods to characterize the dopamine innervations of the nucleus accumbens core and shell in the rat. Concentrations of both dopamine and serotonin were significantly greater in the nucleus accumbens shell than the nucleus accumbens core. Metabolite: amine ratios suggested that both dopamine and serotonin utilization are greater in the core. However, dopamine turnover (as determined by measuring the rate of decline of dopamine after alpha-methyl-p-tyrosine treatment) was not significantly different in the two accumbal sectors. Dopamine concentrations in the two nucleus accumbens sectors were decreased to an equivalent degree at both 4 and 18 h after reserpine administration. In contrast, serotonin concentrations were decreased to a significantly greater degree in the nucleus accumbens core than nucleus accumbens shell at 4 h, but not 18 h, after reserpine administration. Administration of haloperidol increased dopamine utilization in both nucleus accumbens sectors, but augmented utilization to a significantly greater degree in the nucleus accumbens core. Clozapine increased dopamine utilization to an equivalent degree in both nucleus accumbens regions. Short duration immobilization stress selectively increased dopamine utilization in the nucleus accumbens shell. These data indicate that there are significant differences between the nucleus accumbens core and nucleus accumbens shell in basal dopamine metabolism, and indicate that the core and shell dopamine innervations can be distinguished on the basis of response to both pharmacological and environmental challenges.(ABSTRACT TRUNCATED AT 250 WORDS)
A novel protein tyrosine kinase (PTK) substrate, p120, has been previously implicated in ligand-induced signaling through the epidermal growth factor, platelet-derived growth factor and colony-stimulating factor 1 receptors, and in cell transformation by p60v-src. We have isolated a near full-length cDNA encoding murine p120. The encoded protein lacks significant homology with any reported protein, but it contains four copies of an imperfect 42 amino acid repeat that occurs 12.5 times in the protein encoded by Drosophila armadillo (arm), and its direct homologs, human plakoglobin (plak) and Xenopus laevis beta-catenin (beta-cat). The presence of this motif implies that p120 may share at least one aspect of its function with the arm protein and its homologs.