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• W2033780497 abstract "The oocyte-to-embryo transition requires drastic reorganizations within a short timeframe. Recent studies show that, in the nematode Caenorhabditis elegans, phosphotyrosine-binding pseudo-phosphatases are key regulators of this critical developmental transition. The oocyte-to-embryo transition requires drastic reorganizations within a short timeframe. Recent studies show that, in the nematode Caenorhabditis elegans, phosphotyrosine-binding pseudo-phosphatases are key regulators of this critical developmental transition. The transition from an oocyte to an embryo is a profound one, involving major physiological changes. In the nematode Caenorhabditis elegans, the two meiotic divisions that segregate maternal chromosomes are completed within 30 minutes following fertilization. During this period, multiple changes convert the cell from an oocyte-like state to a mitotically-dividing embryo [1Stitzel M.L. Seydoux G. Regulation of the oocyte-to-zygote transition.Science. 2007; 316: 407-408Crossref PubMed Scopus (196) Google Scholar]. The kinase MiniBrain Kinase homolog-2 (MBK-2) is a major driver of many of these changes [2Greenstein D. Lee L.A. Oocyte-to-embryo transition: kinase cabal plots regime change.Curr. Biol. 2006; 16: R93-R95Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. MBK-2 is known to phosphorylate five targets to promote the oocyte-to-embryo transition. It promotes the formation of the mitotic spindle by phosphorylating the katanin MEI-1, thereby inducing its degradation [3Pang K.M. Ishidate T. Nakamura K. Shirayama M. Trzepacz C. Schubert C.M. Priess J.R. Mello C.C. The minibrain kinase homolog, mbk-2, is required for spindle positioning and asymmetric cell division in early C. elegans embryos.Dev. Biol. 2004; 265: 127-139Crossref PubMed Scopus (63) Google Scholar, 4Quintin S. Mains P.E. Zinke A. Hyman A.A. The mbk-2 kinase is required for inactivation of MEI-1/katanin in the one-cell Caenorhabditis elegans embryo.EMBO Rep. 2003; 4: 1175-1181Crossref PubMed Scopus (58) Google Scholar, 5Pellettieri J. Reinke V. Kim S.K. Seydoux G. Coordinate activation of maternal protein degradation during the egg-to-embryo transition in C. elegans.Dev. Cell. 2003; 5: 451-462Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar]. The microtubule-severing activity of MEI-1 is initially required to properly form the two small meiotic spindles; however, MEI-1 must be degraded so that it does not prevent the formation of the larger mitotic spindle [6Srayko M. Buster D.W. Bazirgan O.A. McNally F.J. Mains P.E. MEI-1/MEI-2 katanin-like microtubule severing activity is required for Caenorhabditis elegans meiosis.Genes Dev. 2000; 14: 1072-1084PubMed Google Scholar]. MBK-2 also promotes transcriptional silencing in the zygote by phosphorylating the zinc-finger proteins OMA-1 and OMA-2, activating them to sequester a general transcription factor component [7Guven-Ozkan T. Nishi Y. Robertson S.M. Lin R. Global transcriptional repression in C. elegans germline precursors by regulated sequestration of TAF-4.Cell. 2008; 135: 149-160Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar]. Lastly, MBK-2 contributes to the polarization of the embryo by phosphorylating MEX-5 and MEX-6 to activate their polarity functions [8Nishi Y. Rogers E. Robertson S.M. Lin R. Polo kinases regulate C. elegans embryonic polarity via binding to DYRK2-primed MEX-5 and MEX-6.Development. 2008; 135: 687-697Crossref PubMed Scopus (81) Google Scholar]. MBK-2 must be kept inactive in oocytes, as its premature activation would promote a shift away from the oocyte-like state. Even after fertilization, MBK-2 is tightly regulated so that it is only activated at the end of the first meiotic division. One question that has vexed the field is how MBK-2 activity is regulated. Two new papers by the Singson and Seydoux labs, one in this issue of Current Biology [9Parry J.M. Velarde N.V. Lefkovith A.J. Zegarek M.H. Hang J.S. Ohm J. Klancer R. Maruyama R. Druzhinina M.K. Grant B.D. et al.EGG-4 and EGG-5 link events of the oocyte-to-embryo transition with meiotic progression in C. elegans.Curr. Biol. 2009; 19: 1752-1757Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar] and one in Cell [10Cheng K.C.-C. Klancer R. Singson A. Seydoux G. Regulation of MBK-2/DYRK by CDK-1 and the pseudo-phosphatases EGG-4 and EGG-5 during the oocyte-to-embryo transition.Cell. 2009; 139: 560-572Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar], report evidence that pseudo-phosphatases control the activity of MBK-2 using a strategy that may have widespread implications for other signal transduction pathways. Pseudo-phosphatases are proteins that contain a protein tyrosine phosphatase (PTP) domain but that lack at least one key residue in the catalytic site. These proteins are unable to act as phosphatases, but critically, they are still able to bind to phosphotyrosine residues in proteins [11Hunter T. Anti-phosphatases take the stage.Nat. Genet. 1998; 18: 303-305Crossref PubMed Scopus (48) Google Scholar, 12Wishart M.J. Dixon J.E. Gathering STYX: phosphatase-like form predicts functions for unique protein-interaction domains.Trends Biochem. Sci. 1998; 23: 301-306Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar]. Interestingly, a large percentage of PTP-domain proteins are predicted to be pseudo-phosphatases: 62% of all PTP-domain proteins in C. elegans (57 of 91), and 40% in humans (20 of 51) [13Pils B. Schultz J. Evolution of the multifunctional protein tyrosine phosphatase family.Mol. Biol. Evol. 2004; 21: 625-631Crossref PubMed Scopus (22) Google Scholar]. Animal genomes therefore contain significant numbers of PTP domain proteins that cannot act as phosphatases. The function of these proteins has been largely unexplored. Initially, these proteins were predicted to act as ‘anti-phosphatases’ that bind phosphotyrosine residues to prevent phosphatases from dephosphorylating these sites [11Hunter T. Anti-phosphatases take the stage.Nat. Genet. 1998; 18: 303-305Crossref PubMed Scopus (48) Google Scholar, 12Wishart M.J. Dixon J.E. Gathering STYX: phosphatase-like form predicts functions for unique protein-interaction domains.Trends Biochem. Sci. 1998; 23: 301-306Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar]. But, as described below, the analysis of three C. elegans pseudo-phosphatases, EGG-3, EGG-4 and EGG-5, extend the molecular functions of this class of proteins beyond the role of anti-phosphatase. The pseudo-phosphatase EGG-3 has been linked to the localization of MBK-2 [14Maruyama R. Velarde N.V. Klancer R. Gordon S. Kadandale P. Parry J.M. Hang J.S. Rubin J. Stewart-Michaelis A. Schweinsberg P. et al.EGG-3 regulates cell-surface and cortex rearrangements during egg activation in Caenorhabditis elegans.Curr. Biol. 2007; 17: 1555-1560Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 15Stitzel M.L. Cheng K.C. Seydoux G. Regulation of MBK-2/Dyrk kinase by dynamic cortical anchoring during the oocyte-to-zygote transition.Curr. Biol. 2007; 17: 1545-1554Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar]. In oocytes, MBK-2 is located on the cortex in an inactive state. MBK-2 remains on the cortex until anaphase of meiosis I, when it moves to discrete cytoplasmic foci, the structures of which have not yet been determined. After the meiotic divisions, these foci disappear, resulting in diffuse cytoplasmic localization of the now active MBK-2 (Figure 1). EGG-3 co-localizes with MBK-2 both at the cortex of oocytes and in the cytoplasmic foci present after meiosis I [14Maruyama R. Velarde N.V. Klancer R. Gordon S. Kadandale P. Parry J.M. Hang J.S. Rubin J. Stewart-Michaelis A. Schweinsberg P. et al.EGG-3 regulates cell-surface and cortex rearrangements during egg activation in Caenorhabditis elegans.Curr. Biol. 2007; 17: 1555-1560Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 15Stitzel M.L. Cheng K.C. Seydoux G. Regulation of MBK-2/Dyrk kinase by dynamic cortical anchoring during the oocyte-to-zygote transition.Curr. Biol. 2007; 17: 1545-1554Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar]. EGG-3 physically binds to MBK-2 and acts as an anchor to hold MBK-2 at the cortex. In the absence of egg-3, MBK-2 is cytoplasmic in oocytes, but nevertheless remains inactive (although MBK-2 does become activated slightly sooner after fertilization) [15Stitzel M.L. Cheng K.C. Seydoux G. Regulation of MBK-2/Dyrk kinase by dynamic cortical anchoring during the oocyte-to-zygote transition.Curr. Biol. 2007; 17: 1545-1554Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar]. Therefore, EGG-3 is a major determinant of MBK-2 localization, but is not a significant inhibitor of MBK-2 activity. Parry et al. [9Parry J.M. Velarde N.V. Lefkovith A.J. Zegarek M.H. Hang J.S. Ohm J. Klancer R. Maruyama R. Druzhinina M.K. Grant B.D. et al.EGG-4 and EGG-5 link events of the oocyte-to-embryo transition with meiotic progression in C. elegans.Curr. Biol. 2009; 19: 1752-1757Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar] screened for egg-3-related genes that are expressed in the germline, and discovered two closely related paralogs, egg-4 and egg-5, which encode proteins that also lack a critical PTP catalytic site residue. EGG-4 and EGG-5 are 99% identical and have fully redundant functions; they will be referred to here as ‘EGG-4/5’. EGG-4/5 co-localizes with EGG-3 and MBK-2 on the oocyte cortex. EGG-3 is required to anchor EGG-4/5 to the cortex. In turn, both EGG-3 and EGG-4/5 are required to anchor MBK-2 to the cortex. This localization dependence occurs through direct physical interaction: EGG-3 binds to both EGG-4/5 and MBK-2; and EGG-4/5 binds to MBK-2 [9Parry J.M. Velarde N.V. Lefkovith A.J. Zegarek M.H. Hang J.S. Ohm J. Klancer R. Maruyama R. Druzhinina M.K. Grant B.D. et al.EGG-4 and EGG-5 link events of the oocyte-to-embryo transition with meiotic progression in C. elegans.Curr. Biol. 2009; 19: 1752-1757Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 10Cheng K.C.-C. Klancer R. Singson A. Seydoux G. Regulation of MBK-2/DYRK by CDK-1 and the pseudo-phosphatases EGG-4 and EGG-5 during the oocyte-to-embryo transition.Cell. 2009; 139: 560-572Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar] (Figure 1). Like most kinases, MBK-2 has an ‘activation loop’ that is phosphorylated [10Cheng K.C.-C. Klancer R. Singson A. Seydoux G. Regulation of MBK-2/DYRK by CDK-1 and the pseudo-phosphatases EGG-4 and EGG-5 during the oocyte-to-embryo transition.Cell. 2009; 139: 560-572Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar]. The phosphorylation of the activation loop induces a conformational change in most kinases to allow substrate binding [16Huse M. Kuriyan J. The conformational plasticity of protein kinases.Cell. 2002; 109: 275-282Abstract Full Text Full Text PDF PubMed Scopus (1353) Google Scholar]. Many kinases are controlled by the regulated phosphorylation of their activation loop by other kinases [16Huse M. Kuriyan J. The conformational plasticity of protein kinases.Cell. 2002; 109: 275-282Abstract Full Text Full Text PDF PubMed Scopus (1353) Google Scholar]. In contrast, dual-specificity DYRK kinases, which include MBK-2, are known to autophosphorylate their own activation loop on a tyrosine residue, but only when they are undergoing their initial protein folding [17Lochhead P.A. Sibbet G. Morrice N. Cleghon V. Activation-loop autophosphorylation is mediated by a novel transitional intermediate form of DYRKs.Cell. 2005; 121: 925-936Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar]. Interestingly, when DYRK kinases are fully folded, they lose the ability to phosphorylate tyrosine residues, and can only phosphorylate serine and threonine residues [17Lochhead P.A. Sibbet G. Morrice N. Cleghon V. Activation-loop autophosphorylation is mediated by a novel transitional intermediate form of DYRKs.Cell. 2005; 121: 925-936Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar]. Therefore, DYRK activation loops are only autophosphorylated as the kinases are created. Cheng et al. [10Cheng K.C.-C. Klancer R. Singson A. Seydoux G. Regulation of MBK-2/DYRK by CDK-1 and the pseudo-phosphatases EGG-4 and EGG-5 during the oocyte-to-embryo transition.Cell. 2009; 139: 560-572Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar] found that EGG-4 uses its PTP domain to bind the phosphotyrosine in the activation loop of MBK-2. Biochemical experiments showed that EGG-4 binding inhibits MBK-2 activity by both blocking access to substrates and reducing catalytic activity. Inactivation of egg-4/5 allowed the ectopic activation of MBK-2 in oocytes in 13% of animals [10Cheng K.C.-C. Klancer R. Singson A. Seydoux G. Regulation of MBK-2/DYRK by CDK-1 and the pseudo-phosphatases EGG-4 and EGG-5 during the oocyte-to-embryo transition.Cell. 2009; 139: 560-572Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar]. However, the observation that MBK-2 remained inactive in the oocytes of 87% of egg-4/5 RNAi animals pointed to an additional level of MBK-2 regulation. Cheng et al. [10Cheng K.C.-C. Klancer R. Singson A. Seydoux G. Regulation of MBK-2/DYRK by CDK-1 and the pseudo-phosphatases EGG-4 and EGG-5 during the oocyte-to-embryo transition.Cell. 2009; 139: 560-572Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar] uncovered this second, independent mechanism to control MBK-2. They showed that MBK-2 activation requires phosphorylation on a cyclin dependent kinase-1 (CDK-1) phosphorylation site (Figure 1). If the CDK-1 site is mutated so that it cannot be phosphorylated, MBK-2 never becomes fully active. It is likely that CDK-1 directly phosphorylates MBK-2 in vivo, as purified human CDK-1 can phosphorylate MBK-2 in vitro, and CDK-1 activity is required for the phosphorylation in vivo. To confirm that MBK-2 is redundantly regulated by EGG-4/5 inhibition and CDK-1-dependent phosphorylation, the authors expressed an MBK-2 phospho-mimic mutant that is active without CDK-1 phosphorylation and observed that upon inactivating egg-4/5, the phospho-mimic MBK-2 was now active in the oocytes of 100% of animals. CDK-1 normally becomes active at oocyte maturation [18Boxem M. Srinivasan D.G. van den Heuvel S. The Caenorhabditis elegans gene ncc-1 encodes a cdc2-related kinase required for M phase in meiotic and mitotic cell divisions, but not for S phase.Development. 1999; 126: 2227-2239PubMed Google Scholar], and EGG-4/5 disappears from the cell at the end of the first meiotic division [9Parry J.M. Velarde N.V. Lefkovith A.J. Zegarek M.H. Hang J.S. Ohm J. Klancer R. Maruyama R. Druzhinina M.K. Grant B.D. et al.EGG-4 and EGG-5 link events of the oocyte-to-embryo transition with meiotic progression in C. elegans.Curr. Biol. 2009; 19: 1752-1757Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 10Cheng K.C.-C. Klancer R. Singson A. Seydoux G. Regulation of MBK-2/DYRK by CDK-1 and the pseudo-phosphatases EGG-4 and EGG-5 during the oocyte-to-embryo transition.Cell. 2009; 139: 560-572Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar]. Therefore, the activation of MBK-2 is dually controlled in response to two cell-cycle events: oocyte maturation and the completion of the first meiotic division (Figure 1). A pertinent question is how MBK-2 is released from the inhibition by EGG-4/5. EGG-4/5 disappears from cells at the same time that MBK-2 becomes active, but what mediates its disappearance is not known. A likely scenario involves the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that becomes active at meiotic anaphase I [19Pesin J.A. Orr-Weaver T.L. Regulation of APC/C activators in mitosis and meiosis.Annu. Rev. Cell Dev. Biol. 2008; 24: 475-499Crossref PubMed Scopus (232) Google Scholar, 20Shakes D.C. Sadler P.L. Schumacher J.M. Abdolrasulnia M. Golden A. Developmental defects observed in hypomorphic anaphase-promoting complex mutants are linked to cell cycle abnormalities.Development. 2003; 130: 1605-1620Crossref PubMed Scopus (53) Google Scholar] (Figure 1). APC/C targets the degradation of proteins with a destruction box motif; and both EGG-3 and EGG-4/5 have multiple destruction-box motifs. EGG-3 degradation appears to be mediated by APC/C as it depends on the destruction box motifs and APC/C activity [10Cheng K.C.-C. Klancer R. Singson A. Seydoux G. Regulation of MBK-2/DYRK by CDK-1 and the pseudo-phosphatases EGG-4 and EGG-5 during the oocyte-to-embryo transition.Cell. 2009; 139: 560-572Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar]. It remains to be determined whether EGG-4/5 is similarly regulated by APC/C. These new studies provide the first concrete evidence that the binding of a pseudo-phosphatase directly regulates the activity of a target protein. Interestingly, the phenotypes of egg-4/5 mutants suggest additional functions beyond the regulation of MBK-2. Parry et al. [9Parry J.M. Velarde N.V. Lefkovith A.J. Zegarek M.H. Hang J.S. Ohm J. Klancer R. Maruyama R. Druzhinina M.K. Grant B.D. et al.EGG-4 and EGG-5 link events of the oocyte-to-embryo transition with meiotic progression in C. elegans.Curr. Biol. 2009; 19: 1752-1757Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar] show that inactivation of egg-4/5 produces severe defects in eggshell formation; defects in the polarized actin cap that forms upon sperm entry; a failure to extrude polar bodies during the meiotic divisions; and polyspermy. This latter phenotype is particularly exciting, as it provides a genetic handle with which to study how C. elegans oocytes block the entry of multiple sperm. The block to polyspermy is especially important for nematodes, where large numbers of sperm surround the oocyte as it enters the spermatheca. The study of these additional EGG-4/5 functions may provide further insights into the molecular roles of pseudo-phosphatases. Given the large numbers of pseudo-phosphatases in animals, we suspect that we are just beginning to appreciate the functions of these proteins in dynamic cellular pathways." @default.
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• W2033780497 title "Embryogenesis: Degenerate Phosphatases Control the Oocyte-to-Embryo Transition" @default.
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