ISOLATION AND CHARACTERIZATION OF A HUMAN DUAL-SPECIFICITY PROTEIN-TYROSINE-PHOSPHATASE GENE

Vaccinia phosphatase VH-1 and its mammalian counterparts, including pr otein-tyrosine phosphatases (PTPase) CL100 and VHR, constitute a novel subfamily of protein-tyrosine phosphatases that exhibits dual substra te specificity for phosphotyrosine- and phosphoserine/threonine-contai ning substrates. The expression of human VH-1-like PTPase CL100 is rap idly 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 shor t introns 400-500 base pairs in length. Analysis of the protein sequen ce encoded by each exon revealed that there is a second region of simi larity between CL100 protein and cdc25 in addition to the PTPase catal ytic domain. Promoter analysis of the CL100 gene indicates that an 800 -base pair region flanking the transcriptional initiation site is suff icient to confer a transcriptional response to serum and 12-0-tetradec anoylphorbol-13-acetate stimulation. The CL100 gene is expressed in nu merous tissues, including nonmitotic cells in the brain. Within the br ain, CL100 mRNA is localized in discrete neuronal populations, suggest ing that this PTPase is likely to play a key role in neurotransmission as well as in mitotic signaling. Finally, although extracellular sign al-regulated kinase has recently been shown to act as substrate for CL 100 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.