PAC-1: a Mitogen-Induced Nuclear Protein Tyrosine Phosphatase

Abstract

Tyrosine phosphorylation of proteins is required for signal transduction in cells and for growth regulation. A mitogen-induced gene ( PAC-1 ) has been cloned from human T cells and encodes a 32-kilodalton protein that contains a sequence that defines the enzymatic site of known protein phosphotyrosine phosphatases (PTPases). Other than this sequence, PAC-1 is different from several other known related PTPases exemplified by PTP-1b. PAC-1 is similar to a phosphatase induced by mitogens or heat shock in fibroblasts, a yeast gene, and a vaccinia virus-encoded serine-tyrosine phosphatase (VH1). PAC-1 was predominantly expressed in hematopoietic tissues and localized to the nucleus in transfected COS-7 cells and in mitogen-stimulated T cells.

MKP5, a new member of the MAP kinase phosphatase family, which selectively dephosphorylates stress-activated kinases

“…Two N-terminal charged clusters of amino acids, RRAR-(15)-RAR, have been identi®ed in hVH-3/B23 (Kwak and Dixon, 1995; Ishibashi et al, 1994). Similar clusters are present in the amino acid sequences of MKP-1/CL100 (RRRAK-(14)-RGR) (Keyse and Emslie, 1992), hVH-2/MKP-2/TYP-1 (RRRAK-(15)-RAR) (King et al, 1995;Misra-Press et al, 1995;Guan and Butch, 1995), PAC-1 (RRRAR-(16)-RTR) (Rohan et al, 1993), and MKP-4 (RRLRR-(30)-RRRR) . Although not clear bipartite nuclear localization sequences (Dingwall and Laskey, 1991), these sequences may contribute to the subcellular localization of these phosphatases.…”

“…The subcellular localization of MKP5 di ers from that of the other dual speci®city phosphatases. MKP-1/ CL100, PAC-1, hVH-2/MKP-2/TYP-1 and hVH-3/B23 are localized entirely within the nucleus (Rohan et al, 1993;Guan and Butch, 1995;Kwak and Dixon, 1995;Brondello et al, 1995), MKP-3/PYST1 is entirely cytoplasmic (Muda et al, 1996a;Groom et al, 1996), MKP-4 is mainly cytoplasmic with some punctate staining in the nucleus , while hVH-5/M3/6 is cytosolic or nuclear depending on cell type (Theodosiou et al, 1996). Two N-terminal charged clusters of amino acids, RRAR-(15)-RAR, have been identi®ed in hVH-3/B23 (Kwak and Dixon, 1995; Ishibashi et al, 1994).…”

“…However, phylogenetic analysis of the catalytic domains of the dual-speci®city phosphatases, revealed two major clusters of sequences ( Figure 1b). In one cluster, members (CL100, hVH-2, B23 and PAC-1) share the common characteristic of being localized exclusively in the nucleus of the cell (Keyse and Emslie, 1992;Guan and Butch, 1995;Ishibashi et al, 1994;Rohan et al, 1993). Sequences belonging to the second cluster (PYST-1, PYST-2 and MKP-4), are localized predominantly in the cytoplasm of cells, and also appear to be more speci®c for ERK than other MAP kinases (Groom et al, 1996;Muda et al, 1997).…”

Essential role of calcium in the regulation of MAP kinase phosphatase-1 expression

“…Other members of the VH1 family of dual-speci®city protein phosphatases include VHR (Ishibashi et al, 1992), PAC-1 (Rohan et al, 1993), MKP-2/hVH-2/ TYP-1 (Guan and Butch, 1995;Misra-Press et al, 1995;King et al, 1995), B23/hVH-3 (Ishibashi et al, 1994;Kwak et al, 1995), hVH-5 (Martell et al, 1995) and rVH-6/MKP-3 (Mourey et al, 1996;Muda et al, 1996). These gene products have unique but overlapping tissue distribution patterns.…”

Role of basal calcium in the EGF activation of MAP kinases

“…One possible mechanism that would ®t this function is the Ca 2+ -dependent induction of MAP kinase phosphatases, as described by Cook et al (1997) and Scimeca et al (1997). Several dual phosphatases that dephosphorylate erk-1 and erk-2 have been identi®ed in various cell types and some are known to be immediate early genes expressed following growth factor addition to cells (Guan and Butch, 1995;Keyse and Emslie, 1992;Rohan et al, 1993). Our data are in agreement with that of Cook et al (1997) but indicate that it is basal intracellular Ca 2+ and not growth factor-induced Ca 2+ transients that participate in the control of erk-1 and erk-2 activation.…”