Human Dual Specificity Phosphatase VHR Activates Maturation Promotion Factor and Triggers Meiotic Maturation in Xenopus Oocytes

Bacterially expressed, dual specificity phosphatase VHR protein induced germinal vesicle breakdown (GVBD) when microinjected into Xenopus oocytes, albeit with slower kinetics than that observed in progesterone- or insulin-induced maturation. A mutant VHR protein missing an essential cysteine residue for its in vitro phosphatase activity completely lacked activity in injected oocytes. VHR injection done in conjunction with progesterone or insulin treatment resulted in highly synergized GVBD responses showing much faster kinetics than that produced by VHR or either hormone alone. The delayed kinetics of VHR-induced GVBD and the synergistic responses obtained in the presence of hormones suggested that this protein may be promoting G2/M transition by weakly mimicking the action of cdc25, the dual specificity phosphatase that physiologically activates the maturation promotion factor.Various experimental observations are consistent with such a role for the injected VHR in oocytes: 1) as opposed to hormone-treated oocytes, histone H1 kinase activation is not preceded by MAPK activation in the process of GVBD in VHR-injected oocytes; 2) incubation of purified VHR with highly concentrated cell-free extracts of untreated oocytes resulted in activation of histone H1 kinase activity in the lysates; 3) coinjection of VHR with activated Ras proteins resulted in synergized responses, faster than those produced by either protein alone; 4) coinjection of VHR with the purified amino-terminal SH2 domain of the p85 subunit of phosphatidylinositol 3-kinase (which blocks insulin-induced GVBD) does not affect VHR-induced maturation.The biological actions of VHR in oocytes clearly distinguish it from other dual specificity phosphatases, which have shown inhibitory effects when tested in oocytes. We speculate that VHR may represent a dual specificity phosphatase responsible for activation of cdk-cyclin complex(es) at a still undetermined stage of the cell cycle. Bacterially expressed, dual specificity phosphatase VHR protein induced germinal vesicle breakdown (GVBD) when microinjected into Xenopus oocytes, albeit with slower kinetics than that observed in progesterone- or insulin-induced maturation. A mutant VHR protein missing an essential cysteine residue for its in vitro phosphatase activity completely lacked activity in injected oocytes. VHR injection done in conjunction with progesterone or insulin treatment resulted in highly synergized GVBD responses showing much faster kinetics than that produced by VHR or either hormone alone. The delayed kinetics of VHR-induced GVBD and the synergistic responses obtained in the presence of hormones suggested that this protein may be promoting G2/M transition by weakly mimicking the action of cdc25, the dual specificity phosphatase that physiologically activates the maturation promotion factor. Various experimental observations are consistent with such a role for the injected VHR in oocytes: 1) as opposed to hormone-treated oocytes, histone H1 kinase activation is not preceded by MAPK activation in the process of GVBD in VHR-injected oocytes; 2) incubation of purified VHR with highly concentrated cell-free extracts of untreated oocytes resulted in activation of histone H1 kinase activity in the lysates; 3) coinjection of VHR with activated Ras proteins resulted in synergized responses, faster than those produced by either protein alone; 4) coinjection of VHR with the purified amino-terminal SH2 domain of the p85 subunit of phosphatidylinositol 3-kinase (which blocks insulin-induced GVBD) does not affect VHR-induced maturation. The biological actions of VHR in oocytes clearly distinguish it from other dual specificity phosphatases, which have shown inhibitory effects when tested in oocytes. We speculate that VHR may represent a dual specificity phosphatase responsible for activation of cdk-cyclin complex(es) at a still undetermined stage of the cell cycle. INTRODUCTIONThe process of signal transduction from surface tyrosine kinase receptors to the nucleus is mainly regulated by mechanisms of reversible protein phosphorylation and dephosphorylation. Increasing attention has been focused recently on the family of protein tyrosine phosphatases involved in signaling pathways and regulation of cell proliferation (1Charbonneau H. Tonks N.K. Annu. Rev. Cell Biol. 1992; 8: 463-493Crossref PubMed Scopus (296) Google Scholar, 2Walton K.M. Dixon J.E. Annu. Rev. Biochem. 1993; 62: 101-120Crossref PubMed Scopus (414) Google Scholar). Dual specificity phosphatases constitute a novel subfamily of protein tyrosine phosphatases characterized by their ability to dephosphorylate not only Tyr but also Ser/Thr residues in substrates in vitro. The first described member in this subfamily, cdc25, is known to activate the p34cdc2-cyclin kinase complex that regulates entry into the M phase, through dephosphorylation of specific Tyr and Thr residues (3Millar J.B. Russell P. Cell. 1992; 68: 407-410Abstract Full Text PDF PubMed Scopus (193) Google Scholar). A number of other dual specificity phosphatases have been recently described (4Guan K. Broyles S.S. Dixon J.E. Nature. 1991; 350: 359-362Crossref PubMed Scopus (324) Google Scholar, 5Keyse S.M. Emslie E.A. Nature. 1992; 359: 644-647Crossref PubMed Scopus (568) Google Scholar, 6Alessi D.R. Smythe C. Keyse S.M. Oncogene. 1993; 8: 2015-2020PubMed Google Scholar, 7Charles C.H. Sun H. Lau L.F. Tonks N.K. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 5292-5296Crossref PubMed Scopus (183) Google Scholar, 8Rohan P.J. Davis P. Moskaluk C.A. Kearns M. Krutzsch H. Siebenlist U. Kelly K. Science. 1993; 259: 1763-1766Crossref PubMed Scopus (263) Google Scholar, 9Hannon G.J. Casso D. Beach D. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1731-1735Crossref PubMed Scopus (110) Google Scholar, 10Ward Y. Gupta S. Jensen P. Wartmann M. Davis R.J. Kelly K. Nature. 1994; 367: 651-654Crossref PubMed Scopus (295) Google Scholar). While some of these have been shown to dephosphorylate MAP1( 1The abbreviations used are: MAPmicrotubule-associated proteinGVBDgerminal vesicle breakdownMPFmaturation promotion factorGSTglutathione S-transferasePAGEpolyacrylamide gel electrophoresisMBPmyelin basic protein.) kinase in vivo or in vitro(10Ward Y. Gupta S. Jensen P. Wartmann M. Davis R.J. Kelly K. Nature. 1994; 367: 651-654Crossref PubMed Scopus (295) Google Scholar, 11Nebreda A.R. Hunt T. EMBO J. 1993; 12: 1979-1986Crossref PubMed Scopus (251) Google Scholar, H. C.H. Lau L.F. Tonks N.K. Cell. 1993; Full Text PDF PubMed Scopus Google to with involved in the cell in J. Biochem. Sci. 1994; Full Text PDF PubMed Scopus Google is a dual specificity phosphatase recently in by of T. A. T. Proc. Natl. Acad. Sci. U. S. A. 1993; Scopus Google Scholar). of have to VHR and other protein tyrosine phosphatases, for a which to constitute the to protein tyrosine phosphatases G.J. Casso D. Beach D. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1731-1735Crossref PubMed Scopus (110) Google Scholar, T. A. T. Proc. Natl. Acad. Sci. U. S. A. 1993; Scopus Google Scholar, J. H. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar). is in to and VHR than to the other phosphatases S.M. M. Biochem. Sci. 1993; Full Text PDF PubMed Scopus Google Scholar). in to other of the dual specificity protein tyrosine phosphatase subfamily, VHR specificity in T. A. T. Proc. Natl. Acad. Sci. U. S. A. 1993; Scopus Google Scholar). role is known for this protein tyrosine oocytes are at the G2/M transition of the first or insulin these to and maturation germinal vesicle breakdown in a process that in phosphorylation Science. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). of the with GVBD are by activation of maturation promoting a of M transition in P. Nature. PubMed Scopus Google Scholar, J. T. Biol. Google Scholar). is is a complex of protein and PubMed Scopus Google Scholar, P. Nature. PubMed Scopus Google Scholar, J. T. Biol. Google kinase activity is by cdc25, a dual specificity phosphatase (3Millar J.B. Russell P. Cell. 1992; 68: 407-410Abstract Full Text PDF PubMed Scopus (193) Google Scholar). also that kinase kinase and kinase are essential in the of in activation and maturation A.R. A. Oncogene. 1993; 8: Google Scholar, H. Y. EMBO J. 1994; PubMed Scopus Google oocytes at pathways of activation through progesterone to activity with a in and protein kinase the insulin or a of by tyrosine phosphorylation of their receptors Science. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). Ras and other proteins also have been shown to maturation when microinjected into Xenopus oocytes A.R. A. Oncogene. 1993; 8: Google Scholar, C. D. M. Cell. Full Text PDF PubMed Scopus Google Scholar, M. T. J. Nature. PubMed Scopus Google Scholar, S.M. Cell. Biol. 1991; PubMed Scopus Google Scholar, A.R. D. D. L.F. Science. 1991; PubMed Scopus Google Scholar, A.R. S. Oncogene. 1992; Google Scholar, J. Cell Biol. 1993; PubMed Scopus Google Scholar). of that Ras proteins are essential in insulin-induced maturation Cell. Biol. PubMed Scopus Google Scholar, Science. PubMed Scopus Google Scholar, J.B. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The of and the of it by of into Xenopus oocytes this a experimental for the of the role of in through the cell cycle. the the Xenopus in to in vivo of and Xenopus obtained from and to by of from by stage oocytes into and of and The oocytes to in the treatment and at of of oocytes in in the presence of progesterone or insulin or microinjected into the with of or mutant VHR in microinjected with maturation by the of the nucleus (GVBD) in oocytes with the of the nucleus with the of a in the and a Dixon J.E. Biochem. 1992; PubMed Scopus Google used to and mutant VHR as a protein with and of as described T. A. T. Proc. Natl. Acad. Sci. U. S. A. 1993; Scopus Google Scholar, Dixon J.E. Biochem. 1991; PubMed Scopus Google Scholar). and as by of VHR proteins obtained by of purified protein as described T. A. T. Proc. Natl. Acad. Sci. U. S. A. 1993; Scopus Google and at protein at of activity those the proteins used at a of in of of oocytes as described A.R. A. Oncogene. 1993; 8: Google Scholar). in and and cell-free from untreated oocytes for in vitro as described Cell Biol. 1992; Scopus Google with some oocytes in and in the and The oocytes to and and at at for and at a at for at The by a and and of and M to this The protein of these extracts of in oocytes, histone H1 kinase as described A.R. A. Oncogene. 1993; 8: Google Scholar). of extracts in a of with of histone and of for at histone H1 by on and in the histone H1 on the with a basic protein kinase as described J. Biol. Full Text PDF Google but of in the presence of protein kinase A of extracts with of at for and on and as kinase activation in highly concentrated cell-free extracts in the presence of VHR as of purified VHR protein with of as described and and of on at and at and with an of in kinase H1 kinase and kinase described C. J. Cell Biol. 1991; PubMed Scopus Google the or in kinase activation also by of in done kinase VHR of Xenopus by the VHR T. A. T. Proc. Natl. Acad. Sci. U. S. A. 1993; Scopus Google injected into oocytes, and its biological effects The injected protein highly and in the of the injected oocytes specific of observed that injection of VHR resulted in GVBD incubation the of GVBD induced by VHR delayed as to progesterone or VHR-induced GVBD in but in the The of GVBD by microinjected VHR and on its activity injection of or an mutant that phosphatase activity T. A. T. Proc. Natl. Acad. Sci. U. S. A. 1993; Scopus Google to maturation experimental process of GVBD induced by VHR also highly on the of VHR in the injected oocytes. GVBD observed when than of purified VHR injected and VHR in of GVBD in oocytes at pathways that in activation of the kinase complex and progesterone the activity and protein kinase the insulin or of phosphorylation by tyrosine phosphorylation of the specific Science. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). of the of Ras in insulin-induced maturation Cell. Biol. PubMed Scopus Google Scholar, Science. PubMed Scopus Google Scholar, J.B. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google to VHR with of of these microinjected VHR in oocytes that also with either insulin or shown in microinjected VHR produced a in the of GVBD induced by either progesterone or insulin at a of of either The synergistic of VHR when of either hormone used obtained and of the for insulin and The maturation and VHR is in to the shown by other phosphatases, which GVBD kinase activation D.R. Smythe C. Keyse S.M. Oncogene. 1993; 8: 2015-2020PubMed Google Scholar, N.K. Cell. Biol. PubMed Scopus Google Scholar). The activity of VHR and its with progesterone and insulin are consistent with a VHR at a to progesterone- and pathways of of in has been shown that of phosphorylation activation of kinase and the kinase of are essential for the process of GVBD induced by insulin or progesterone A.R. A. Oncogene. 1993; 8: Google Scholar, H. Y. EMBO J. 1994; PubMed Scopus Google Scholar, M. Proc. Natl. Acad. Sci. U. S. A. 1992; PubMed Scopus Google Scholar). We that microinjected Ras proteins activate these in the of protein in a process in which the of activation of kinase the of activation of the kinase of P. Nature. PubMed Scopus Google Scholar, J. T. Biol. Google as as histone H1 kinase activity A.R. A. Oncogene. 1993; 8: Google Scholar). purified Ras proteins have been shown to activate kinase in vitro when to cell-free extracts P. Nature. PubMed Scopus Google Scholar, M. Proc. Natl. Acad. Sci. U. S. A. 1992; PubMed Scopus Google to activation of and the process of GVBD induced by microinjected obtained in in which the kinetics of GVBD the kinetics of activation of the kinase and and the kinase as histone H1 kinase and in of in vivo activation of histone H1 and kinase in oocytes microinjected with the kinetics of GVBD and activation of H1 and and in VHR-injected oocytes. obtained in of GVBD in oocytes microinjected with of histone H1 kinase in extracts of oocytes microinjected with VHR oocytes used activity is shown in to the activity in untreated oocytes at The H1 kinase is with the of maturation oocytes with a of for the of the H1 kinase in on a of histone H1 protein is by the kinase in of oocytes used as described as to in of untreated oocytes at from obtained by the kinase in the of the untreated oocytes with a of for the with kinase of the extracts of in described for hormone-treated oocytes P. Nature. PubMed Scopus Google Scholar, J. T. Biol. Google Scholar, A.R. A. Oncogene. 1993; 8: Google observed that the in H1 kinase activity with the of maturation by microinjected VHR with and as described for oocytes Nature. 1992; PubMed Scopus Google H1 kinase activity of oocytes induced to by VHR at GVBD and to a that the VHR-injected oocytes a maturation process Nature. 1992; PubMed Scopus Google process of VHR-induced GVBD also by the activation of kinase activity that be either by kinase of or by specific the kinase to or oocytes, in which the of kinase activation clearly histone H1 kinase activation A.R. A. Oncogene. 1993; 8: Google the of kinase activation in VHR-injected oocytes histone H1 kinase activity in with a in the histone H1 kinase activity and of by VHR to of the ability of VHR to its phosphatase activity 1) and the kinetics of kinase activation this process 2) suggested that VHR be at the of activation of mimicking in a the action of cdc25, dual specificity phosphatase known to be the of the kinase activity in the complex this G2/M transition (3Millar J.B. Russell P. Cell. 1992; 68: 407-410Abstract Full Text PDF PubMed Scopus (193) Google Scholar, P. Nature. PubMed Scopus Google Scholar, J. T. Biol. Google Scholar). to this to purified VHR activate kinase in when to highly concentrated cell-free experimental to those used with Ras and A.R. Hunt T. EMBO J. 1993; 12: 1979-1986Crossref PubMed Scopus (251) Google Scholar, H. Y. EMBO J. 1994; PubMed Scopus Google Scholar, M. Proc. Natl. Acad. Sci. U. S. A. 1992; PubMed Scopus Google Scholar, J. Cell. Biol. 1993; PubMed Scopus Google observed that of purified VHR to highly concentrated resulted in the in vitro activation of the kinase histone H1 kinase activation the of incubation in the presence of a at A and The of activation of kinase activity the activation of histone H1 with a at it not to it has been shown that MAPK be a for J.E. M. Cell. Biol. 1991; PubMed Scopus Google Scholar, Y. K. S. T. H. K. H. EMBO J. 1991; PubMed Scopus Google Scholar, J. J. S. Cell. Biol. 1991; PubMed Scopus Google these as an that the kinase activation observed may be to the histone H1 kinase of in vitro histone H1 and kinase in extracts in the presence of activity of highly concentrated extracts incubation with VHR phosphatase at at the and for the as described of histone H1 kinase activity as described of histone H1 kinase activity a on the gel shown in A. activity is shown in to the activity in untreated extracts at extracts at of treatment with a of kinase activity of at the and as described untreated with a of for the of GVBD and on by VHR a activation of the kinase by at a of the GVBD to progesterone- and that the it be that of the of of progesterone and insulin pathways also with VHR-induced of such a not be to VHR-induced tested those by VHR with activated Ras protein A.R. A. Oncogene. 1993; 8: Google which GVBD by in the insulin of activation Cell. Biol. PubMed Scopus Google Scholar, Science. PubMed Scopus Google Scholar, J.B. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). We also VHR with a to the amino-terminal SH2 domain of the p85 subunit of phosphatidylinositol 3-kinase which blocks insulin-induced GVBD Cell. Biol. 1993; PubMed Scopus Google by at a the activated tyrosine kinase and of Ras activation by that coinjection of activated Ras and VHR proteins resulted in a of the of as to injection with either VHR or Ras alone. the amino-terminal SH2 p85 completely insulin-induced GVBD GVBD the kinetics of GVBD observed in oocytes with VHR and the p85 SH2 from that of oocytes injected with VHR that the not maturation induced by of a microinjected VHR weakly the phosphatase activity of cdc25, the kinase complex and the process of maturation in Xenopus of and of GVBD on maturation by of Ras showing of GVBD in oocytes microinjected of purified of Ras of VHR and of obtained in of the amino-terminal SH2 domain of the p85 subunit of of phosphatidylinositol 3-kinase of GVBD in oocytes as with insulin alone; microinjected with of of phosphatidylinositol 3-kinase and in the presence of microinjected with of with of VHR and of for to the of the than of for VHR action in Xenopus oocytes. GVBD in Xenopus oocytes be through of phosphorylation by either progesterone kinase or insulin tyrosine that in activation of the of M transition in P. Nature. PubMed Scopus Google Scholar, J. T. Biol. Google Scholar). of the kinase kinase is a for activation in vivo A.R. A. Oncogene. 1993; 8: Google Scholar, H. Y. EMBO J. 1994; PubMed Scopus Google Scholar, M. Proc. Natl. Acad. Sci. U. S. A. 1992; PubMed Scopus Google kinase also be a for by activated J.E. M. Cell. Biol. 1991; PubMed Scopus Google Scholar, Y. K. S. T. H. K. H. EMBO J. 1991; PubMed Scopus Google Scholar, J. J. S. Cell. Biol. 1991; PubMed Scopus Google Scholar). Ras proteins are essential in insulin-induced maturation Cell. Biol. PubMed Scopus Google Scholar, Science. PubMed Scopus Google Scholar, J.B. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google and also activation of but not in in vitro M. Proc. Natl. Acad. Sci. U. S. A. 1992; PubMed Scopus Google Scholar). Ras in the of protein to GVBD through a process kinase activation kinase activation A.R. A. Oncogene. 1993; 8: Google Scholar). A the observed that VHR by mimicking the of cdc25, the phosphatase of (3Millar J.B. Russell P. Cell. 1992; 68: 407-410Abstract Full Text PDF PubMed Scopus (193) Google Scholar). that of in the of GVBD with microinjected VHR a microinjected but not the VHR have a role is that the microinjected VHR to a its phosphatase activity a role of the inhibitory that be its phosphatase activity the Xenopus oocytes, that cell proliferation the cell and their and be for and protein kinase GVBD) and tyrosine or GVBD) signaling pathways to maturation Science. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, P. Nature. PubMed Scopus Google Scholar, J. T. Biol. Google of phosphorylation by either progesterone kinase or insulin tyrosine in the activation of kinase the of M transition in P. Nature. PubMed Scopus Google Scholar, J. T. Biol. Google the tyrosine and protein kinase signaling pathways have been at injection of in some of these pathways may their of action in those signaling pathways that the purified VHR dual specificity phosphatase protein induced GVBD in the microinjected oocytes. not in of showing that other tyrosine phosphatases or dual specificity phosphatases the process of maturation or of activation of kinase in Xenopus oocytes D.R. Smythe C. Keyse S.M. Oncogene. 1993; 8: 2015-2020PubMed Google Scholar, N.K. Cell. Biol. PubMed Scopus Google Scholar). GVBD by VHR to maturation in the presence of of progesterone or of its ability to GVBD on the presence of of with effects when than the VHR effects and specific a phosphatase VHR mutant not the The kinetics and of as as the for of that VHR-induced GVBD is its with cdc25, the dual specificity phosphatase that physiologically transition from to M in Xenopus oocytes P. Nature. PubMed Scopus Google Scholar, J. T. Biol. Google and also GVBD when injected into the oocytes J. Cell. 1991; Full Text PDF PubMed Scopus Google activity of VHR also in of the tyrosine phosphatase activity shown by this protein in vitro on a of substrates for the insulin T. A. T. Proc. Natl. Acad. Sci. U. S. A. 1993; Scopus Google Scholar). is that of VHR into the of oocytes, for dephosphorylation the of hormone at the surface and the activation of dephosphorylation of or of such for the inhibitory effects on GVBD by other phosphatases such as or D.R. Smythe C. Keyse S.M. Oncogene. 1993; 8: 2015-2020PubMed Google Scholar, N.K. Cell. Biol. PubMed Scopus Google Scholar). microinjected phosphatase N.K. Cell. Biol. PubMed Scopus Google has been to dephosphorylate at the insulin and other D.R. Smythe C. Keyse S.M. Oncogene. 1993; 8: 2015-2020PubMed Google and which is for insulin induced GVBD H. Y. EMBO J. 1994; PubMed Scopus Google that VHR not GVBD but it and that the of phosphorylation in injected and oocytes that the injected VHR is not its phosphatase that VHR is to a substrates dephosphorylation in of GVBD are not The nucleus is such a that be tested when specific of are with a in which the injected VHR through a of to activates the complex of by mimicking the of the The kinetics and of the GVBD induced by VHR be with such a The that VHR activates the histone H1 kinase in vitro in extracts this is of that Ras and only activate but not in in vitro with extracts A.R. Hunt T. EMBO J. 1993; 12: 1979-1986Crossref PubMed Scopus (251) Google Scholar, M. Proc. Natl. Acad. Sci. U. S. A. 1992; PubMed Scopus Google Scholar, J. Cell. Biol. 1993; PubMed Scopus Google VHR from and not involved in the process of G2/M transition in oocytes, this dual specificity phosphatase may be a of the involved in of the kinase activity of cdk-cyclin involved in of the cell cycle. The of of these at of the cell has been recently J. Biochem. Sci. 1994; Full Text PDF PubMed Scopus Google Scholar, J. Science. 1994; PubMed Scopus Google Scholar, J. Science. 1994; PubMed Scopus Google Scholar). a dual specificity phosphatase with to VHR has been recently shown to with in G.J. Casso D. Beach D. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1731-1735Crossref PubMed Scopus (110) Google Scholar). of the effects of VHR in may in such a is INTRODUCTIONThe process of signal transduction from surface tyrosine kinase receptors to the nucleus is mainly regulated by mechanisms of reversible protein phosphorylation and dephosphorylation. Increasing attention has been focused recently on the family of protein tyrosine phosphatases involved in signaling pathways and regulation of cell proliferation (1Charbonneau H. Tonks N.K. Annu. Rev. Cell Biol. 1992; 8: 463-493Crossref PubMed Scopus (296) Google Scholar, 2Walton K.M. Dixon J.E. Annu. Rev. Biochem. 1993; 62: 101-120Crossref PubMed Scopus (414) Google Scholar). Dual specificity phosphatases constitute a novel subfamily of protein tyrosine phosphatases characterized by their ability to dephosphorylate not only Tyr but also Ser/Thr residues in substrates in vitro. The first described member in this subfamily, cdc25, is known to activate the p34cdc2-cyclin kinase complex that regulates entry into the M phase, through dephosphorylation of specific Tyr and Thr residues (3Millar J.B. Russell P. Cell. 1992; 68: 407-410Abstract Full Text PDF PubMed Scopus (193) Google Scholar). A number of other dual specificity phosphatases have been recently described (4Guan K. Broyles S.S. Dixon J.E. Nature. 1991; 350: 359-362Crossref PubMed Scopus (324) Google Scholar, 5Keyse S.M. Emslie E.A. Nature. 1992; 359: 644-647Crossref PubMed Scopus (568) Google Scholar, 6Alessi D.R. Smythe C. Keyse S.M. Oncogene. 1993; 8: 2015-2020PubMed Google Scholar, 7Charles C.H. Sun H. Lau L.F. Tonks N.K. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 5292-5296Crossref PubMed Scopus (183) Google Scholar, 8Rohan P.J. Davis P. Moskaluk C.A. Kearns M. Krutzsch H. Siebenlist U. Kelly K. Science. 1993; 259: 1763-1766Crossref PubMed Scopus (263) Google Scholar, 9Hannon G.J. Casso D. Beach D. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1731-1735Crossref PubMed Scopus (110) Google Scholar, 10Ward Y. Gupta S. Jensen P. Wartmann M. Davis R.J. Kelly K. Nature. 1994; 367: 651-654Crossref PubMed Scopus (295) Google Scholar). While some of these have been shown to dephosphorylate MAP1( 1The abbreviations used are: MAPmicrotubule-associated proteinGVBDgerminal vesicle breakdownMPFmaturation promotion factorGSTglutathione S-transferasePAGEpolyacrylamide gel electrophoresisMBPmyelin basic protein.) kinase in vivo or in vitro(10Ward Y. Gupta S. Jensen P. Wartmann M. Davis R.J. Kelly K. Nature. 1994; 367: 651-654Crossref PubMed Scopus (295) Google Scholar, 11Nebreda A.R. Hunt T. EMBO J. 1993; 12: 1979-1986Crossref PubMed Scopus (251) Google Scholar, H. C.H. Lau L.F. Tonks N.K. Cell. 1993; Full Text PDF PubMed Scopus Google to with involved in the cell in J. Biochem. Sci. 1994; Full Text PDF PubMed Scopus Google is a dual specificity phosphatase recently in by of T. A. T. Proc. Natl. Acad. Sci. U. S. A. 1993; Scopus Google Scholar). of have to VHR and other protein tyrosine phosphatases, for a which to constitute the to protein tyrosine phosphatases G.J. Casso D. Beach D. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1731-1735Crossref PubMed Scopus (110) Google Scholar, T. A. T. Proc. Natl. Acad. Sci. U. S. A. 1993; Scopus Google Scholar, J. H. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar). is in to and VHR than to the other phosphatases S.M. M. Biochem. Sci. 1993; Full Text PDF PubMed Scopus Google Scholar). in to other of the dual specificity protein tyrosine phosphatase subfamily, VHR specificity in T. A. T. Proc. Natl. Acad. Sci. U. S. A. 1993; Scopus Google Scholar). role is known for this protein tyrosine oocytes are at the G2/M transition of the first or insulin these to and maturation germinal vesicle breakdown in a process that in phosphorylation Science. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). of the with GVBD are by activation of maturation promoting a of M transition in P. Nature. PubMed Scopus Google Scholar, J. T. Biol. Google Scholar). is is a complex of protein and PubMed Scopus Google Scholar, P. Nature. PubMed Scopus Google Scholar, J. T. Biol. Google kinase activity is by cdc25, a dual specificity phosphatase (3Millar J.B. Russell P. Cell. 1992; 68: 407-410Abstract Full Text PDF PubMed Scopus (193) Google Scholar). also that kinase kinase and kinase are essential in the of in activation and maturation A.R. A. Oncogene. 1993; 8: Google Scholar, H. Y. EMBO J. 1994; PubMed Scopus Google oocytes at pathways of activation through progesterone to activity with a in and protein kinase the insulin or a of by tyrosine phosphorylation of their receptors Science. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). Ras and other proteins also have been shown to maturation when microinjected into Xenopus oocytes A.R. A. Oncogene. 1993; 8: Google Scholar, C. D. M. Cell. Full Text PDF PubMed Scopus Google Scholar, M. T. J. Nature. PubMed Scopus Google Scholar, S.M. Cell. Biol. 1991; PubMed Scopus Google Scholar, A.R. D. D. L.F. Science. 1991; PubMed Scopus Google Scholar, A.R. S. Oncogene. 1992; Google Scholar, J. Cell Biol. 1993; PubMed Scopus Google Scholar). of that Ras proteins are essential in insulin-induced maturation Cell. Biol. PubMed Scopus Google Scholar, Science. PubMed Scopus Google Scholar, J.B. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The of and the of it by of into Xenopus oocytes this a experimental for the of the role of in through the cell cycle. the the Xenopus in to in vivo of