- Email: [email protected]
Plague, pox and tyrosine dephosphorylation
N.K. TONKS
CELL SIGNALLING
Plague, pox and tyrosine
dephosphorylation
The tyrosine phosphatases are a diverse family of proteins. Two newly identified members seem to be involved in the mechanism of infection by the Ipathogenic bacterium, Yersinia, and the pox virus, vaccinia. “For I will at this time send all my phgues upon thine heart and upon thy servants, and upon tbypeople; that thou mayest know that there is none like me in all the earth : Exodus 9:14 Although the authors of Exodus will not have appreciated it at the time, they were providing one of the iirst documentations of the artion of a protein tyrosine phosphatase! Kunliang Guan and Jack Dixon [l] have noted that an essential virulence determinant of the genus of bacteria Yersinia - the causative agent of the plague or ‘black death’ - contains a signature sequence found in members of the protein tyrosine phosphatase family, and is active as a phosphatas;e. The net level of phosphate detected in tyrosyl residues in a target protein in uiz~oreflects the balance between the activity of protein tyrosine kinases and protein tyrosine phosphatases. Although the tyrosine phosphatases are essential components of the regulatory networks controlled by reversible tyrosine phosphorylation they have, until recently, remained relatively neglected. When the Iirst tyrosine phosphatase to be isolated in homogeneous form, a 37kD enzyme termed PTPlB purilied from human placenta [2], was sequenced, two striking features were observed. First, no structural relationship was detected between PTPlB and the serine/threonine phosphatases or acid and alkaline phosphatases. This is unlike the situation for the protein kinases, which all seem to be derived from a common ancestor. Second, marked similarity was detected with the sequence of the tandemrepeated intracellular domains of the leukocyte common antigen, CD45 [3]. CD45 is a transmembrane glycoprotein found exclusively in haematopoietic cells, the extracellular segment of which bears the hallmarks of a ligand binding structure. This ratised the exciting possibility that CD45 may be a member of a novel family of receptors with the capacity to initiate signal transduction pathways through the ligand-modulated dephosphorylation of tyrosyl residues in proteins. CD45, has been shown to possess intrinsic tyrosine phosphatase activity [4]. Since these observations, the floodgates have opened and a wide variety of both transmembrane, receptor-like and non-transmembrane tyrosine phosphatases have been described in a diverse array of tissues and cell lines (Fig. 1). At least ten distinct transmembrane tyrosine phosphatases have been identiiied. With the exception of one isoform (termed HPTPj3 [5]) the intracellular segments of these species are similar, comprising two homologous
Volume 1
Number 4
‘1991
domains (coloured green in Fig. 1). It is in their extracellular segments that they display diversity, presumably reflecting a concomitant diversity in the ligands to which they respond. Originally recognized as a CD45-related member of the immunoglobulin superfamily, the lirst receptor tyrosine phosphatase to be identified in non-haematopoietic cells was IAR (Fig. la), the extracellular segment of which displays structural similarity to the neural cell adhesion molecules (NCAMs), comprising three immunoglobulin-like (coloured blue) and eight fibronectin type III-like (coloured yellow) domains [ 61. Perhaps homophilic interactions between LAR molecules on adjacent cells may regulate adhesion phenomena, such as contact inhibition of cell growth, through modulation of the tyrosine phosphatase activity of their intracellular segments. The size of the extracellular segments of the receptor tyrosine phosphatases varies dramatically, from 27 residues in HPTPE and 123 residues in the glycosylated external domain of HPTPcl, to the 1234residue NCAM-like segment of LAR and the 16 repeated fibronectin type-III domains in the 1599residue external portion of HPTPj.%Although one may anticipate homophilic interactions between LAR molecules and interaction between the external segment of HPTP p and soluble ligands, or even members of the integrin family, there are no data available to suggest the identity of the ligands for these receptor molecules. In contrast to the receptor-like tyrosine phosphatases, the non-transmembrane forms have been somewhat more elusive, Sequence and mutation analyses have revealed a conserved segment of -250 residues, which probably encompasses the catalytic domain in members of the tyrosine phosphatase family. These enzymes are sensitive to thiol-directed reagents and within the catalytic domains there is a cysteinyl residue, located in a highly conserved sequence, that has an essential role in activity. When Guan and Dixon searched the National Biomedi cal Research Foundation (NBRF) database for structures related to the tyrosine phosphatase domain, they noted that a protein tenned Yop2b (Yersinia outer membrane protein) displayed such a conserved region, most notably in the segment surrounding the highly conserved cysteine [ 1] . The Yop2b protein is encoded by the YOPH gene, located on a 70 kb plasmid in the bacterium Yersiniapseudotuberculosis, one of three Yersinia species. X pseudo tubercuks~ mostly affects rodents and causes diarrhoea and emaciation, ultimately resulting in death due to septicaemia. y enterocolitica is a human pathogen causing
gastrointestinal syndromes of varying severities. It is infection by Y pest& that causes the plague. The virulence of all three species depends on proteins encoded by the 70 kb plasmid. Yop2b of Y: pseudotuberculosis displays 99% sequence identity to Yop51 of Y enterocolitica; their relationship to the tyrosine phosphatases was substantiated when &an and Dixon expressed recombinant Yop51 and showed that it encoded an active enzyme [ 11, Like the other members of the tyrosine phosphatase family, ~0~51 displays specihcity for the dephosphorylation of tyrosyl residues in proteins. Subsequent studies, in collaboration with Bliska and Falkow, demonstrated that the tyrosine phosphatase activity of Yop2b is essential for the virulence of Y pseudotuberculosis [ 71. A mutant generated by site-directed mutagenesis ln which the essential cysteinyl residue (Cys403) was replaced by alanyl, to generate an inactive phosphatase, displayed substantially reduced capacity to induce disease in a murine model system in which bacterial growth in the spleen was assessed. The Yop tyrosine phosphatase must cross the host membrane to be functional, although the details of the processes involved are still sketchy. It is bellieved that, following expression, the Yop protein is secreted by the bacterium and taken up by the host cell by phagocytosis. Whether this secretion process is mediated by attachment of the bacterium to receptors on the host cell surface, involving bacterial invasin molecules and host integrins, remains unclear. But, using a murine macrophage cell line, J774A.1, Bliska et al. [7] have shown that the Yop tyrosine phosphatase does induce changes in endogenous protein tyrosine phosphorylation, most notably leading to the dephosphorylation of proteins of 120 kD and 60 kD. A detailed understanding of the effects of the YOPH-encoded protein on signal transduction in infected cells will await the identification of these proteins. As the authors thernselves have noted [ 11, bacteria are not known to contain tyrosine phosphorylated proteins, which raises questions as to the origin of the plasmidencoded Yop proteins. The situation is reminiscent of that pertaining to olncogenes in retroviruses, as typified by S-C;V-S-Chas been shown to be derived from a normal cellular gene, the proto-oncogene C-SK. This situation is repeated in at least 20 other retroviral oncogenes [ES].Perhaps a precursor of tirsiniu acquired, and possibly mutated, a normal cellular tyrosine phosphatase. Two other well chaLracterized non-transmembrane tyrosine phosphatases are PTPlB - a truncated version of which was first isolated from human placenta [2] - and TCPTP, identiIied as a cDNA from a human peripheral T-cell library and now known to exhibit a broad tissue distribution (Fig. lb). Their structures can be described in terms of two segments: an N-terminal catalytic domain, and a C-terminal sejgrnent that seems to be important in the control of both activity and intracellular localization [9]. In contrast, within the Yop proteins the catalytic domain is C-terminal with a non-catalytic segment at the N terminus. Whether this latter segment has a regulatory function remains to be established. A similar architecture is observed in PYP1, a tyrosine phosphatase identified re-
260
cently in Scbizosuccbaromyces pombe [lo]. In addition, an isoform termed PTPHl has been identified in HeIa cells in which the tyrosine phosphatase domain is also C-tem-iinal but the N-terminal segment displays homology to the motifs in the cytoskeleton-associated proteins, band 4.1, ezrin and talin (Fig. 1b, coloured red) that seem to be responsible for directing their localization to interfaces between the plasma membrane and the cytoskeleton [ 111. It has been proposed that PTPHl may exert its effects in structures such as focal adhesion plaques [ 111. Thus, a general theme is becoming apparent among the tyrosine phosphatases; distinct structural motifs within the protein may, at least in part, control specificity by restricting intracellular localization. In this regard it will be interesting to dissect the role of the N-terminal segment of the Yop proteins.
HPTPp
Fig. 1. Some
members
of the
family
of
protein
tyrosine
phos-
phatases.
Following their initial studies, Dixon and colleagues looked for other pathogenic organisms that may ex-
@ 1991 Current Biology
ploit protein tyrosine dlephosphorylation in their mechanism of action. They searched the NBRF database again, but this time with the sequence GPIWHCSAGVGRTG (single-letter amino-acid code) surrounding the essential cysteinyl residue, presumably in the active site of the tyrosine phosphatases. Using this approach, they identified a distant relationship between the tyrosine phosphatases and an open reading frame in the genome of the pox virus vaccinia, termed WI1 [ 127. In contrast to the other tyrosine phosphatases, the VHl protein is very small (171 residues, m.olecular weight -2OkD; Fig. lb) apparently encoding only a catalytic domain. They expressed the VHl protein and found that unlike the other tyrosine phosphatases, which are specific for phosphotyrosyl residues, VH1 displays tyrosine or serine phosphatase activity against art&&l substrates in vitro. In both cases, mutation of the active site cysteinyl (CysllO) to seryl abolished activity. One would speculate that following infection, as in the case of the Yop protein, WI1 disrupts the normal signal transduction machinery of the host cell through aberrant dephosphorylation of tyrosyl residues. However, its substrates have still to be lidentiIied. Many have noted a similarity, though somewhat limited [ 131, between VHl and the product of the cdc25 gene of S.pornbe, implying that the latter may also be a phosphatase. The p80&25 protein is intimately associated with the dephosphorylation of Tyr15 in the ATPbinding site of the eukaryotic cell cycle regulator p34@. This dephosphorylation event activates p34a as a protein kinase, for example toward histone Hl as substrate, and drives the cell into mitosis [ 141, Evidence is accumulating to suggest that p80&25 is in fact an enzyme that acts directly on ~34”~ [15]. In higher eukaryotes, Thr14 in p34d2 is also phosphorylated, suggesting that the activation of the kinase will require either the coordinated action of a tyrosine phosphatase and an enzyme with specificity for seryl/threonyl residues or the action of a single broad-specificity enzyme with the capacity to dephosphorylate both Thr14 and Tyrl5. In this regard, it is interesting to recall that only VIII, with specificity for set-y1(and probably threonyl) as well as tyrosyl residues, displays structural similarity to p8Ocdc25.Whether p80&25 does, in fact, dephosphorylate both Thr14 and Tyrl5 in p34&2 and whether p34”1”2 is a substrate for WI1 in vaccinia-iiected cells remains to be established. In conclusion, I believe that we are only viewing the tip of a very large iceberg. Research into the protein-tyrosine phosphatases is in an exploratory phase where the main progress is being made in the identitication of new isoforms. HOWWZK, through the characterization of
Volume 1
Number 4. 1991
the structure, function and mode of regulation of members of this family, a more sophisticated understanding of the physiological roles of tyrosine phosphorylation is anticipated. References 1. GUAN K, DD(ON JE: Protein tyrosine phosphatase activity of an essential virulence determinant in Yersinia. Science 1998, 249553-556. 2.
TONKS NK, Dnnz CD, FIXHER EH: Puritication of the major protein tyrosine phosphatases of human placenta. J Blol Cbem
3.
CHARBONWRAU H, TOW NK, WAISH KA, LECHER EH: The leukocyte common antigen (CD45): A putative receptor-linked protein tyrosine phosphatase. Proc Nat1 Acad Sci USA 1988,
1988,
263~6722-6737.
85:7182-7186. TONICS NK,
4.
CHARBONNFAUH, DILIZ CD, FISCHER EH, WALSH KA: Demonstration that the leukocyte common antigen CD45 is a protein tyrosine phosphatase.. Biodjemfi+’ 1988,
5.
KRUEGER NX,
27B695-8701. STREW
lLMB0
6.
7.
8. 9.
J 1990,
diversity and evoprotein tyrosine phosphatases.
M, SAITO H: Structural
lution of human receptor-like 9:3241-3252.
M, KREUGER NX, HALL LR, SC~SSMAN SF, SArrO H: A new member of the immunoglobulin superfamily that has a cytoplasmic region homologous to tbe leukocyte common antigen. J Eap Med 1988, l&3:1523-1530. BLWA JB, GUAN K, DD(ON JE, FAJXOW S: Tyrosine phosphate hydrolysis of host proteins by an essential Yersinia virulence determinant. Proc Nat1 Acad Sci USA 1991, 88:1187-1191. VARMUSH: Retroviruses. Science 1988, 240~1427-1435. COOL DE, TONKS NK, CHARBONNEXU H, FIXHER EH, KRRBS EG: Expression of a human T-cell protein tyrosine phosphatase in baby hamster kidney cells. Pnx Nat1 Acad Sci USA 1930, STR!XJIJ
87:728&7284.
10. OTTRJE S, CHERNOFF J, HANNIG G, HOFFMAN cs, ER~SON RL: A fission yeast gene encoding a protein with features of the protein tyrosine phosphatases. Proc Nat1 Acud Sci USA 1991, m3455-3459. 11.
YANG Q, TONKS NK: Isolation of a cDNA clone encoding a human protein tyrosine phosphatase with homology to the cytoskeletal-associated proteins band 4.1, ezrin and talon. Proc
12.
GUAN K, BROYLES SS, DIXONJE: A ‘fyr/Ser protein phosphatase encoded by vaccinia virus. Nature 1991, 3503359-362. MORRNOS, NURSEP: Clues to action of cdc25 protein. Nature 1991, 351:194. NURSEP: Universal control mechanism regulating onset Of M-phase. Nature 1990, 344:503-508. ~TANSFELDu, ~ASBB .~c, FRSQUR~D, CAVADOREJC, PICARDA SADHUK, RLJSSELL P, DORREM: Dephosphorylation and activation of a p3W%zyclin B complex in vitro by human cdc25 protein. Nature 1991, 351:242-245.
Nat1 Acad
13. 14. 15.
Sci USA 1991,
88~5949-5953.
N.K. Tanks, Cold Spring Harbor Laboratory, PO Box 100, Cold Spring Harbor, New York 11724, USA
261
CELL SIGNALLING
Plague, pox and tyrosine
dephosphorylation
The tyrosine phosphatases are a diverse family of proteins. Two newly identified members seem to be involved in the mechanism of infection by the Ipathogenic bacterium, Yersinia, and the pox virus, vaccinia. “For I will at this time send all my phgues upon thine heart and upon thy servants, and upon tbypeople; that thou mayest know that there is none like me in all the earth : Exodus 9:14 Although the authors of Exodus will not have appreciated it at the time, they were providing one of the iirst documentations of the artion of a protein tyrosine phosphatase! Kunliang Guan and Jack Dixon [l] have noted that an essential virulence determinant of the genus of bacteria Yersinia - the causative agent of the plague or ‘black death’ - contains a signature sequence found in members of the protein tyrosine phosphatase family, and is active as a phosphatas;e. The net level of phosphate detected in tyrosyl residues in a target protein in uiz~oreflects the balance between the activity of protein tyrosine kinases and protein tyrosine phosphatases. Although the tyrosine phosphatases are essential components of the regulatory networks controlled by reversible tyrosine phosphorylation they have, until recently, remained relatively neglected. When the Iirst tyrosine phosphatase to be isolated in homogeneous form, a 37kD enzyme termed PTPlB purilied from human placenta [2], was sequenced, two striking features were observed. First, no structural relationship was detected between PTPlB and the serine/threonine phosphatases or acid and alkaline phosphatases. This is unlike the situation for the protein kinases, which all seem to be derived from a common ancestor. Second, marked similarity was detected with the sequence of the tandemrepeated intracellular domains of the leukocyte common antigen, CD45 [3]. CD45 is a transmembrane glycoprotein found exclusively in haematopoietic cells, the extracellular segment of which bears the hallmarks of a ligand binding structure. This ratised the exciting possibility that CD45 may be a member of a novel family of receptors with the capacity to initiate signal transduction pathways through the ligand-modulated dephosphorylation of tyrosyl residues in proteins. CD45, has been shown to possess intrinsic tyrosine phosphatase activity [4]. Since these observations, the floodgates have opened and a wide variety of both transmembrane, receptor-like and non-transmembrane tyrosine phosphatases have been described in a diverse array of tissues and cell lines (Fig. 1). At least ten distinct transmembrane tyrosine phosphatases have been identiiied. With the exception of one isoform (termed HPTPj3 [5]) the intracellular segments of these species are similar, comprising two homologous
Volume 1
Number 4
‘1991
domains (coloured green in Fig. 1). It is in their extracellular segments that they display diversity, presumably reflecting a concomitant diversity in the ligands to which they respond. Originally recognized as a CD45-related member of the immunoglobulin superfamily, the lirst receptor tyrosine phosphatase to be identified in non-haematopoietic cells was IAR (Fig. la), the extracellular segment of which displays structural similarity to the neural cell adhesion molecules (NCAMs), comprising three immunoglobulin-like (coloured blue) and eight fibronectin type III-like (coloured yellow) domains [ 61. Perhaps homophilic interactions between LAR molecules on adjacent cells may regulate adhesion phenomena, such as contact inhibition of cell growth, through modulation of the tyrosine phosphatase activity of their intracellular segments. The size of the extracellular segments of the receptor tyrosine phosphatases varies dramatically, from 27 residues in HPTPE and 123 residues in the glycosylated external domain of HPTPcl, to the 1234residue NCAM-like segment of LAR and the 16 repeated fibronectin type-III domains in the 1599residue external portion of HPTPj.%Although one may anticipate homophilic interactions between LAR molecules and interaction between the external segment of HPTP p and soluble ligands, or even members of the integrin family, there are no data available to suggest the identity of the ligands for these receptor molecules. In contrast to the receptor-like tyrosine phosphatases, the non-transmembrane forms have been somewhat more elusive, Sequence and mutation analyses have revealed a conserved segment of -250 residues, which probably encompasses the catalytic domain in members of the tyrosine phosphatase family. These enzymes are sensitive to thiol-directed reagents and within the catalytic domains there is a cysteinyl residue, located in a highly conserved sequence, that has an essential role in activity. When Guan and Dixon searched the National Biomedi cal Research Foundation (NBRF) database for structures related to the tyrosine phosphatase domain, they noted that a protein tenned Yop2b (Yersinia outer membrane protein) displayed such a conserved region, most notably in the segment surrounding the highly conserved cysteine [ 1] . The Yop2b protein is encoded by the YOPH gene, located on a 70 kb plasmid in the bacterium Yersiniapseudotuberculosis, one of three Yersinia species. X pseudo tubercuks~ mostly affects rodents and causes diarrhoea and emaciation, ultimately resulting in death due to septicaemia. y enterocolitica is a human pathogen causing
gastrointestinal syndromes of varying severities. It is infection by Y pest& that causes the plague. The virulence of all three species depends on proteins encoded by the 70 kb plasmid. Yop2b of Y: pseudotuberculosis displays 99% sequence identity to Yop51 of Y enterocolitica; their relationship to the tyrosine phosphatases was substantiated when &an and Dixon expressed recombinant Yop51 and showed that it encoded an active enzyme [ 11, Like the other members of the tyrosine phosphatase family, ~0~51 displays specihcity for the dephosphorylation of tyrosyl residues in proteins. Subsequent studies, in collaboration with Bliska and Falkow, demonstrated that the tyrosine phosphatase activity of Yop2b is essential for the virulence of Y pseudotuberculosis [ 71. A mutant generated by site-directed mutagenesis ln which the essential cysteinyl residue (Cys403) was replaced by alanyl, to generate an inactive phosphatase, displayed substantially reduced capacity to induce disease in a murine model system in which bacterial growth in the spleen was assessed. The Yop tyrosine phosphatase must cross the host membrane to be functional, although the details of the processes involved are still sketchy. It is bellieved that, following expression, the Yop protein is secreted by the bacterium and taken up by the host cell by phagocytosis. Whether this secretion process is mediated by attachment of the bacterium to receptors on the host cell surface, involving bacterial invasin molecules and host integrins, remains unclear. But, using a murine macrophage cell line, J774A.1, Bliska et al. [7] have shown that the Yop tyrosine phosphatase does induce changes in endogenous protein tyrosine phosphorylation, most notably leading to the dephosphorylation of proteins of 120 kD and 60 kD. A detailed understanding of the effects of the YOPH-encoded protein on signal transduction in infected cells will await the identification of these proteins. As the authors thernselves have noted [ 11, bacteria are not known to contain tyrosine phosphorylated proteins, which raises questions as to the origin of the plasmidencoded Yop proteins. The situation is reminiscent of that pertaining to olncogenes in retroviruses, as typified by S-C;V-S-Chas been shown to be derived from a normal cellular gene, the proto-oncogene C-SK. This situation is repeated in at least 20 other retroviral oncogenes [ES].Perhaps a precursor of tirsiniu acquired, and possibly mutated, a normal cellular tyrosine phosphatase. Two other well chaLracterized non-transmembrane tyrosine phosphatases are PTPlB - a truncated version of which was first isolated from human placenta [2] - and TCPTP, identiIied as a cDNA from a human peripheral T-cell library and now known to exhibit a broad tissue distribution (Fig. lb). Their structures can be described in terms of two segments: an N-terminal catalytic domain, and a C-terminal sejgrnent that seems to be important in the control of both activity and intracellular localization [9]. In contrast, within the Yop proteins the catalytic domain is C-terminal with a non-catalytic segment at the N terminus. Whether this latter segment has a regulatory function remains to be established. A similar architecture is observed in PYP1, a tyrosine phosphatase identified re-
260
cently in Scbizosuccbaromyces pombe [lo]. In addition, an isoform termed PTPHl has been identified in HeIa cells in which the tyrosine phosphatase domain is also C-tem-iinal but the N-terminal segment displays homology to the motifs in the cytoskeleton-associated proteins, band 4.1, ezrin and talin (Fig. 1b, coloured red) that seem to be responsible for directing their localization to interfaces between the plasma membrane and the cytoskeleton [ 111. It has been proposed that PTPHl may exert its effects in structures such as focal adhesion plaques [ 111. Thus, a general theme is becoming apparent among the tyrosine phosphatases; distinct structural motifs within the protein may, at least in part, control specificity by restricting intracellular localization. In this regard it will be interesting to dissect the role of the N-terminal segment of the Yop proteins.
HPTPp
Fig. 1. Some
members
of the
family
of
protein
tyrosine
phos-
phatases.
Following their initial studies, Dixon and colleagues looked for other pathogenic organisms that may ex-
@ 1991 Current Biology
ploit protein tyrosine dlephosphorylation in their mechanism of action. They searched the NBRF database again, but this time with the sequence GPIWHCSAGVGRTG (single-letter amino-acid code) surrounding the essential cysteinyl residue, presumably in the active site of the tyrosine phosphatases. Using this approach, they identified a distant relationship between the tyrosine phosphatases and an open reading frame in the genome of the pox virus vaccinia, termed WI1 [ 127. In contrast to the other tyrosine phosphatases, the VHl protein is very small (171 residues, m.olecular weight -2OkD; Fig. lb) apparently encoding only a catalytic domain. They expressed the VHl protein and found that unlike the other tyrosine phosphatases, which are specific for phosphotyrosyl residues, VH1 displays tyrosine or serine phosphatase activity against art&&l substrates in vitro. In both cases, mutation of the active site cysteinyl (CysllO) to seryl abolished activity. One would speculate that following infection, as in the case of the Yop protein, WI1 disrupts the normal signal transduction machinery of the host cell through aberrant dephosphorylation of tyrosyl residues. However, its substrates have still to be lidentiIied. Many have noted a similarity, though somewhat limited [ 131, between VHl and the product of the cdc25 gene of S.pornbe, implying that the latter may also be a phosphatase. The p80&25 protein is intimately associated with the dephosphorylation of Tyr15 in the ATPbinding site of the eukaryotic cell cycle regulator p34@. This dephosphorylation event activates p34a as a protein kinase, for example toward histone Hl as substrate, and drives the cell into mitosis [ 141, Evidence is accumulating to suggest that p80&25 is in fact an enzyme that acts directly on ~34”~ [15]. In higher eukaryotes, Thr14 in p34d2 is also phosphorylated, suggesting that the activation of the kinase will require either the coordinated action of a tyrosine phosphatase and an enzyme with specificity for seryl/threonyl residues or the action of a single broad-specificity enzyme with the capacity to dephosphorylate both Thr14 and Tyrl5. In this regard, it is interesting to recall that only VIII, with specificity for set-y1(and probably threonyl) as well as tyrosyl residues, displays structural similarity to p8Ocdc25.Whether p80&25 does, in fact, dephosphorylate both Thr14 and Tyrl5 in p34&2 and whether p34”1”2 is a substrate for WI1 in vaccinia-iiected cells remains to be established. In conclusion, I believe that we are only viewing the tip of a very large iceberg. Research into the protein-tyrosine phosphatases is in an exploratory phase where the main progress is being made in the identitication of new isoforms. HOWWZK, through the characterization of
Volume 1
Number 4. 1991
the structure, function and mode of regulation of members of this family, a more sophisticated understanding of the physiological roles of tyrosine phosphorylation is anticipated. References 1. GUAN K, DD(ON JE: Protein tyrosine phosphatase activity of an essential virulence determinant in Yersinia. Science 1998, 249553-556. 2.
TONKS NK, Dnnz CD, FIXHER EH: Puritication of the major protein tyrosine phosphatases of human placenta. J Blol Cbem
3.
CHARBONWRAU H, TOW NK, WAISH KA, LECHER EH: The leukocyte common antigen (CD45): A putative receptor-linked protein tyrosine phosphatase. Proc Nat1 Acad Sci USA 1988,
1988,
263~6722-6737.
85:7182-7186. TONICS NK,
4.
CHARBONNFAUH, DILIZ CD, FISCHER EH, WALSH KA: Demonstration that the leukocyte common antigen CD45 is a protein tyrosine phosphatase.. Biodjemfi+’ 1988,
5.
KRUEGER NX,
27B695-8701. STREW
lLMB0
6.
7.
8. 9.
J 1990,
diversity and evoprotein tyrosine phosphatases.
M, SAITO H: Structural
lution of human receptor-like 9:3241-3252.
M, KREUGER NX, HALL LR, SC~SSMAN SF, SArrO H: A new member of the immunoglobulin superfamily that has a cytoplasmic region homologous to tbe leukocyte common antigen. J Eap Med 1988, l&3:1523-1530. BLWA JB, GUAN K, DD(ON JE, FAJXOW S: Tyrosine phosphate hydrolysis of host proteins by an essential Yersinia virulence determinant. Proc Nat1 Acad Sci USA 1991, 88:1187-1191. VARMUSH: Retroviruses. Science 1988, 240~1427-1435. COOL DE, TONKS NK, CHARBONNEXU H, FIXHER EH, KRRBS EG: Expression of a human T-cell protein tyrosine phosphatase in baby hamster kidney cells. Pnx Nat1 Acad Sci USA 1930, STR!XJIJ
87:728&7284.
10. OTTRJE S, CHERNOFF J, HANNIG G, HOFFMAN cs, ER~SON RL: A fission yeast gene encoding a protein with features of the protein tyrosine phosphatases. Proc Nat1 Acud Sci USA 1991, m3455-3459. 11.
YANG Q, TONKS NK: Isolation of a cDNA clone encoding a human protein tyrosine phosphatase with homology to the cytoskeletal-associated proteins band 4.1, ezrin and talon. Proc
12.
GUAN K, BROYLES SS, DIXONJE: A ‘fyr/Ser protein phosphatase encoded by vaccinia virus. Nature 1991, 3503359-362. MORRNOS, NURSEP: Clues to action of cdc25 protein. Nature 1991, 351:194. NURSEP: Universal control mechanism regulating onset Of M-phase. Nature 1990, 344:503-508. ~TANSFELDu, ~ASBB .~c, FRSQUR~D, CAVADOREJC, PICARDA SADHUK, RLJSSELL P, DORREM: Dephosphorylation and activation of a p3W%zyclin B complex in vitro by human cdc25 protein. Nature 1991, 351:242-245.
Nat1 Acad
13. 14. 15.
Sci USA 1991,
88~5949-5953.
N.K. Tanks, Cold Spring Harbor Laboratory, PO Box 100, Cold Spring Harbor, New York 11724, USA
261