Functional characterization of a protein tyrosine phosphatase and its interaction with cellular proteins involved in signal transduction

Abstract

Phosphorylation of proteins on tyrosyl residues is an important mechanism for many newlinesignal transduction pathways controlling cell proliferation, differentiation and development. newlineAlthough the phosphotyrosine content of cellular proteins is the net result of the opposing newlineeffects of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), most newlineinvestigators have concentrated on the PTKs, many of which were cloned and sequenced nearly newlinetwo decades ago. Initially, PTPs were thought to be mere household-enzymes that were newlineubiquitously expressed and had low substrate specificity. Following purification and sequencing newlineof the first PTP, PTP1B and subsequent identification of CD45 as a transmembrane PTP, it newlinebecame clear that PTPs are a diverse family of enzymes with many members that have different newlinesubstrate specificities, are regulated differently and are differentially expressed. newlineThe non-transmembrane protein tyrosine phosphatase PTP-S/TC-PTP is ubiquitously newlineexpressed. In rat cells four different forms of this phosphatase are generated from the primary newlinetranscript by alternative splicing. Two of these major forms, PTP-82 and PTP-84 (also known as newlineTC45 and TC48, respectively) are expressed in rat as well as human cells. PTP-82 is located newlinemainly in the cell nucleus, partly in association with chromatin possibly through its interaction newlinewith DNA. The noncatalytic sequences at the carboxy terminal end of PTP-82 and PTP-84 newlinedetermine their subcellular location, substrate specificity, enzyme activity and interaction with newlineDNA and nuclear matrix. PTP-S mRNA is transiently increased upon mitogenic stimulation of a newlinevariety of cells in vitro. During liver regeneration after partial hepatectomy both the major newlineisoforms PTP-82 and PTP-S4 are transiently induced in G1 phase. PTP-82 is specifically newlinephosphorylated on its C-terminal region during mitosis by CK2 or a CK2-Iike enzyme. PTP-S newlinedeficient mice show poor T and B cell proliferative responses and defects in bone marrow newlinehematopoiesis.