Volume 271, Number 43, Issue of October 25, 1996 pp. 26755-26761
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Two Splice Variants of a Tyrosine Phosphatase Differ in Substrate Specificity, DNA Binding, and Subcellular Location

(Received for publication, April 29, 1996, and in revised form, July 9, 1996)

From the Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India

Four different forms of a non-receptor type protein-tyrosine phosphatase are generated by alternative splicing; two of these forms (PTP-S2 and PTP-S4) are major forms, which are expressed in rat as well as human cells. Here we report that PTP-S2 binds to nonspecific DNA in vitro and localizes in the nucleus upon transfection in HeLa cells. PTP-S4 does not bind to nonspecific DNA and shows perinuclear and cytoplasmic localization. Removal of the C-terminal 34 amino acids of PTP-S4 gives rise to a truncated protein, which binds to nonspecific DNA and localizes to the nucleus. PTP-S4, but not PTP-S2, interacts strongly with the isolated nuclear matrix. The two forms of this tyrosine phosphatase show different substrate specificity in vitro, a feature novel to splice variants of tyrosine phosphatases. Mitogenic stimulation induces mRNAs for PTP-S2 as well as for PTP-S4 in the G₁ phase during liver regeneration. These results suggest that alternative splicing gives rise to two protein-tyrosine phosphatases with distinct substrate specificities and subcellular locations. The 34 amino acids at the C terminus of PTP-S4 play a critical role in determining substrate specificity, subcellular location, and interaction with nuclear matrix and DNA.

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