Isolation and characterization of a human dual specificity protein-tyrosine phosphatase gene.
Vaccinia phosphatase VH-1 and its mammalian counterparts, including protein-tyrosine phosphatases (PTPase) CL100 and VHR, constitute a novel subfamily of protein-tyrosine phosphatases that exhibits dual substrate specificity for phosphotyrosine- and phosphoserine/threonine-containing substrates. The expression of human VH-1-like PTPase CL100 is rapidly inducible by mitogen stimulation and oxidative stress, suggesting that this gene is transcriptionally regulated. In order to study the mechanism underlying this transcriptional regulation, we isolated the first human gene of this subfamily, the CL100 gene, and characterized its promoter. The gene consists of four exons intervened by three short introns 400-500 base pairs in length. Analysis of the protein sequence encoded by each exon revealed that there is a second region of similarity between CL100 protein and cdc25 in addition to the PTPase catalytic domain. Promoter analysis of the CL100 gene indicates that an 800-base pair region flanking the transcriptional initiation site is sufficient to confer a transcriptional response to serum and 12-O-tetradecanoylphorbol-13-acetate stimulation. The CL100 gene is expressed in numerous tissues, including nonmitotic cells in the brain. Within the brain, CL100 mRNA is localized in discrete neuronal populations, suggesting that this PTPase is likely to play a key role in neurotransmission as well as in mitotic signaling. Finally, although extracellular signal-regulated kinase has recently been shown to act as substrate for CL100 in vitro, we find no clear correspondence between the distribution of extracellular signal-regulated kinase and CL100 mRNA in the brain. The potential significance of a second cdc25 homology domain of CL100 is discussed.
Kwak
S P
SP
Department of Biological Chemistry, University of Michigan, Ann Arbor 48109-0606.
Hakes
D J
DJ
Martell
K J
KJ
Dixon
J E
JE
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000201:enzymology; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D002889:Chromosomes, Human, Pair 2; D002895:Chromosomes, Human, Pair 5; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic; D015894:Genome, Human; D015698:Genomic Library; D006367:HeLa Cells; D015186:Hominidae / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D008934:Mitogens / Q000494:pharmacology; D008969:Molecular Sequence Data; D009928:Organ Specificity; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic / Q000187:drug effects
D017931:DNA Primers; D008934:Mitogens; D012333:RNA, Messenger; D017027:Protein Tyrosine Phosphatases