RHO GTPases activate CIT (Homo sapiens)

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1, 2, 5, 14, 16...12, 16, 30361, 2, 5321431cytosolRHOC PRC1 MYL6 RHOA,RHOB,RHOC,RAC1:GTP:CITMYH14 RHOB RAC1 RHOA,RHOB,RHOC,RAC1:GTP:CIT:KIF14:PRC1ATPCIT CIT GTP RHOC RHOB RHOA MYH11 RHOA CIT-3 GTP MYH9 RHOA,RHOB,RHOC,RAC1:GTPGTP RHOB CDKN1B CDKN1BPPP1R12B Myosin phosphataseADPMYH14 p-T19,S20-MRLC-smooth muscle/non-muscle myosin IICIT PRC1MYH9 RHO GTPases activatePKNsMYL6 RHOA,RHOB,RHOC,RAC1:GTP:CIT-3:DLG4PPP1CB RAC1 Smoothmuscle/non-musclemyosin IIMYL12B DLG4 CITRHOC CIT:CDKN1BRHOC MYH11 RHOA,RHOB,RHOC,RAC1:GTP:CIT-3DLG4RHOB p-T19,S20-MYL9 RHOA MYH10 RAC1 MYL9 KIF14RAC1 GTP p-T19,S20-MYL12B GTP RHOA CIT RHO GTPases ActivateROCKsMYH10 RHOB KIF14 RHOC CIT-3RHOA RAC1 CIT-3 CIT-3 PPP1R12A 14311, 2, 512, 16, 30319-11, 13, 19...363, 4, 6-8, 15...


Description

Citron kinase (CIT) or citron RHO-interacting kinase (CRIK) shares similarities with ROCK kinases. Like ROCK, it consists of a serine/threonine kinase domain, a coiled-coil region, a RHO-binding domain, a cysteine rich region and a plekstrin homology (PH) domain, but additionally features a proline-rich region and a PDZ-binding domain. A shorter splicing isoform of CIT, citron-N, is specifically expressed in the nervous system and lacks the kinase domain. Citron-N is a component of the post-synaptic density, where it binds to the PDZ domains of the scaffolding protein PDS-95/SAP90 (Zhang et al. 2006).

While the binding of CIT to RHO GTPases RHOA, RHOB, RHOC and RAC1 is well established (Madaule et al. 1995), the mechanism of CIT activation by GTP-bound RHO GTPases has not been elucidated. There are indications that CIT may be activated through autophosphorylation in the presence of active forms of RHO GTPases (Di Cunto et al. 1998). CIT appears to phosphorylate the myosin regulatory light chain (MRLC), the only substrate identified to date, on the same residues that are phosphorylated by ROCKs, but it has not been established yet how this relates to activation by RHO GTPases (Yamashiro et al. 2003). CIT and RHOA are implicated to act together in Golgi apparatus organization through regulation of the actin cytoskeleton (Camera et al. 2003). CIT is also involved in the regulation of cytokinesis through its interaction with KIF14 (Gruneberg et al. 2006, Bassi et al. 2013, Watanabe et al. 2013) and p27(Kip1) (Serres et al. 2012). View original pathway at:Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 5625900
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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Ontology Terms

 

Bibliography

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  2. Gruneberg U, Neef R, Li X, Chan EH, Chalamalasetty RB, Nigg EA, Barr FA.; ''KIF14 and citron kinase act together to promote efficient cytokinesis.''; PubMed Europe PMC
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  5. Bassi ZI, Audusseau M, Riparbelli MG, Callaini G, D'Avino PP.; ''Citron kinase controls a molecular network required for midbody formation in cytokinesis.''; PubMed Europe PMC
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  11. Sumi T, Matsumoto K, Nakamura T.; ''Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase.''; PubMed Europe PMC
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  14. Serres MP, Kossatz U, Chi Y, Roberts JM, Malek NP, Besson A.; ''p27(Kip1) controls cytokinesis via the regulation of citron kinase activation.''; PubMed Europe PMC
  15. Owen D, Lowe PN, Nietlispach D, Brosnan CE, Chirgadze DY, Parker PJ, Blundell TL, Mott HR.; ''Molecular dissection of the interaction between the small G proteins Rac1 and RhoA and protein kinase C-related kinase 1 (PRK1).''; PubMed Europe PMC
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  19. Amano M, Nakayama M, Kaibuchi K.; ''Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity.''; PubMed Europe PMC
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  21. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K.; ''Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase)''; PubMed Europe PMC
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  23. Yoshinaga C, Mukai H, Toshimori M, Miyamoto M, Ono Y.; ''Mutational analysis of the regulatory mechanism of PKN: the regulatory region of PKN contains an arachidonic acid-sensitive autoinhibitory domain.''; PubMed Europe PMC
  24. Hamaguchi T, Ito M, Feng J, Seko T, Koyama M, Machida H, Takase K, Amano M, Kaibuchi K, Hartshorne DJ, Nakano T.; ''Phosphorylation of CPI-17, an inhibitor of myosin phosphatase, by protein kinase N.''; PubMed Europe PMC
  25. Kato T, Gotoh Y, Hoffmann A, Ono Y.; ''Negative regulation of constitutive NF-kappaB and JNK signaling by PKN1-mediated phosphorylation of TRAF1.''; PubMed Europe PMC
  26. Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K.; ''Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase).''; PubMed Europe PMC
  27. Leung T, Chen XQ, Manser E, Lim L.; ''The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton.''; PubMed Europe PMC
  28. Palmer RH, Dekker LV, Woscholski R, Le Good JA, Gigg R, Parker PJ.; ''Activation of PRK1 by phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. A comparison with protein kinase C isotypes.''; PubMed Europe PMC
  29. Camera P, da Silva JS, Griffiths G, Giuffrida MG, Ferrara L, Schubert V, Imarisio S, Silengo L, Dotti CG, Di Cunto F.; ''Citron-N is a neuronal Rho-associated protein involved in Golgi organization through actin cytoskeleton regulation.''; PubMed Europe PMC
  30. Zhang W, Vazquez L, Apperson M, Kennedy MB.; ''Citron binds to PSD-95 at glutamatergic synapses on inhibitory neurons in the hippocampus.''; PubMed Europe PMC
  31. Madaule P, Furuyashiki T, Reid T, Ishizaki T, Watanabe G, Morii N, Narumiya S.; ''A novel partner for the GTP-bound forms of rho and rac.''; PubMed Europe PMC
  32. Yamashiro S, Totsukawa G, Yamakita Y, Sasaki Y, Madaule P, Ishizaki T, Narumiya S, Matsumura F.; ''Citron kinase, a Rho-dependent kinase, induces di-phosphorylation of regulatory light chain of myosin II.''; PubMed Europe PMC
  33. Misaki K, Mukai H, Yoshinaga C, Oishi K, Isagawa T, Takahashi M, Ohsumi K, Kishimoto T, Ono Y.; ''PKN delays mitotic timing by inhibition of Cdc25C: possible involvement of PKN in the regulation of cell division.''; PubMed Europe PMC
  34. Hutchinson CL, Lowe PN, McLaughlin SH, Mott HR, Owen D.; ''Differential binding of RhoA, RhoB, and RhoC to protein kinase C-related kinase (PRK) isoforms PRK1, PRK2, and PRK3: PRKs have the highest affinity for RhoB.''; PubMed Europe PMC
  35. Mukai H, Toshimori M, Shibata H, Takanaga H, Kitagawa M, Miyahara M, Shimakawa M, Ono Y.; ''Interaction of PKN with alpha-actinin.''; PubMed Europe PMC
  36. Di Cunto F, Calautti E, Hsiao J, Ong L, Topley G, Turco E, Dotto GP.; ''Citron rho-interacting kinase, a novel tissue-specific ser/thr kinase encompassing the Rho-Rac-binding protein Citron.''; PubMed Europe PMC

History

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101486view11:34, 1 November 2018ReactomeTeamreactome version 66
101023view21:14, 31 October 2018ReactomeTeamreactome version 65
100558view19:48, 31 October 2018ReactomeTeamreactome version 64
100106view16:33, 31 October 2018ReactomeTeamreactome version 63
99656view15:04, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93930view13:45, 16 August 2017ReactomeTeamreactome version 61
93516view11:25, 9 August 2017ReactomeTeamreactome version 61
89080view07:49, 22 August 2016EgonwOntology Term : 'signaling pathway' added !
86613view09:22, 11 July 2016ReactomeTeamreactome version 56
83172view10:16, 18 November 2015ReactomeTeamVersion54
81542view13:05, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CDKN1B ProteinP46527 (Uniprot-TrEMBL)
CDKN1BProteinP46527 (Uniprot-TrEMBL)
CIT ProteinO14578 (Uniprot-TrEMBL)
CIT-3 ProteinO14578-3 (Uniprot-TrEMBL) CIT-3 (CIT-N, Citron-N, Citron) is the splice isoform of CIT kinase that lacks the kinase domain and is specifically expressed in the brain
CIT-3ComplexR-HSA-5671992 (Reactome)
CIT:CDKN1BComplexR-HSA-5671981 (Reactome)
CITComplexR-HSA-5671920 (Reactome)
DLG4 ProteinP78352 (Uniprot-TrEMBL)
DLG4ProteinP78352 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
KIF14 ProteinQ15058 (Uniprot-TrEMBL)
KIF14ProteinQ15058 (Uniprot-TrEMBL)
MYH10 ProteinP35580 (Uniprot-TrEMBL)
MYH11 ProteinP35749 (Uniprot-TrEMBL)
MYH14 ProteinQ7Z406 (Uniprot-TrEMBL)
MYH9 ProteinP35579 (Uniprot-TrEMBL)
MYL12B ProteinO14950 (Uniprot-TrEMBL)
MYL6 ProteinP60660 (Uniprot-TrEMBL)
MYL9 ProteinP24844 (Uniprot-TrEMBL)
Myosin phosphataseComplexR-HSA-419080 (Reactome) All known myosin phosphatases consist of PP1 beta and both a large and a small myosin phosphatase targetting (Mypt) subunit. The large Mypt targets PP1 beta to myosin and determines the substrate specifity of the phosphatase. The Large Mypt subunit is encoded by one of three human genes, PPP1R12A (MYPT1), PPP1R12B (MYPT2) and PPP1R12C. Only MYPT1 is represented here. The small subunit is an alternative transcript of MYPT2. The function of the small Mypt subunit remains unclear, but because it is known to interact directly with myosin and the large Mypt it is thought to have an unspecified regulatory role.
PPP1CB ProteinP62140 (Uniprot-TrEMBL)
PPP1R12A ProteinO14974 (Uniprot-TrEMBL)
PPP1R12B ProteinO60237 (Uniprot-TrEMBL)
PRC1 ProteinO43663 (Uniprot-TrEMBL)
PRC1ProteinO43663 (Uniprot-TrEMBL)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RHO GTPases Activate ROCKsPathwayR-HSA-5627117 (Reactome) RHO associated, coiled-coil containing protein kinases ROCK1 and ROCK2 consist of a serine/threonine kinase domain, a coiled-coil region, a RHO-binding domain and a plekstrin homology (PH) domain interspersed with a cysteine-rich region. The PH domain inhibits the kinase activity of ROCKs by an intramolecular fold. ROCKs are activated by binding of the GTP-bound RHO GTPases RHOA, RHOB and RHOC to the RHO binding domain of ROCKs (Ishizaki et al. 1996, Leung et al. 1996), which disrupts the autoinhibitory fold. Once activated, ROCK1 and ROCK2 phosphorylate target proteins, many of which are involved in the stabilization of actin filaments and generation of actin-myosin contractile force. ROCKs phosphorylate LIM kinases LIMK1 and LIMK2, enabling LIMKs to phosphorylate cofilin, an actin depolymerizing factor, and thereby regulate the reorganization of the actin cytoskeleton (Ohashi et al. 2000, Sumi et al. 2001). ROCKs phosphorylate MRLC (myosin regulatory light chain), which stimulates the activity of non-muscle myosin II (NMM2), an actin-based motor protein involved in cell migration, polarity formation and cytokinesis (Amano et al. 1996, Riento and Ridley 2003, Watanabe et al. 2007, Amano et al. 2010). ROCKs also phosphorylate the myosin phosphatase targeting subunit (MYPT1) of MLC phosphatase, inhibiting the phosphatase activity and preventing dephosphorylation of MRLC. This pathway acts synergistically with phosphorylation of MRLC by ROCKs towards stimulation of non-muscle myosin II activity (Kimura et al. 1996, Amano et al. 2010).
RHO GTPases activate PKNsPathwayR-HSA-5625740 (Reactome) Protein kinases N (PKN), also known as protein kinase C-related kinases (PKR) feature a C-terminal serine/threonine kinase domain and three RHO-binding motifs at the N-terminus. RHO GTPases RHOA, RHOB, RHOC and RAC1 bind PKN1, PKN2 and PKN3 (Maesaki et al. 1999, Zhong et al. 1999, Owen et al. 2003, Modha et al. 2008, Hutchinson et al. 2011, Hutchinson et al. 2013), bringing them in proximity to the PIP3-activated co-activator PDPK1 (PDK1) (Flynn et al. 2000, Torbett et al. 2003). PDPK1 phosphorylates PKNs on a highly conserved threonine residue in the kinase activation loop, which is a prerequisite for PKN activation. Phosphorylation of other residues might also be involved in activation (Flynn et al. 2000, Torbett et al. 2003, Dettori et al. 2009). PKNs are activated by fatty acids like arachidonic acid and phospholipids in vitro, but the in vivo significance of this activation remains unclear (Palmer et al. 1995, Yoshinaga et al. 1999).

PKNs play important roles in diverse functions, including regulation of cell cycle, receptor trafficking, vesicle transport and apoptosis. PKN is also involved in the ligand-dependent transcriptional activation by the androgen receptor. More than 20 proteins and several peptides have been shown to be phosphorylated by PKN1 and PKN2, including CPI-17 (Hamaguchi et al. 2000), alpha-actinin (Mukai et al. 1997), adducin (Collazos et al. 2011), CDC25C (Misaki et al. 2001), vimentin (Matsuzawa et al. 1997), TRAF1 (Kato et al. 2008), CLIP170 (Collazos et al. 2011) and EGFR (Collazos et al. 2011). There are no known substrates for PKN3 (Collazos et al. 2011).

RHOA ProteinP61586 (Uniprot-TrEMBL)
RHOA,RHOB,RHOC,RAC1:GTP:CIT-3:DLG4ComplexR-HSA-5672002 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTP:CIT-3ComplexR-HSA-5672001 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTP:CIT:KIF14:PRC1ComplexR-HSA-5671969 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTP:CITComplexR-HSA-5625899 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTPComplexR-HSA-8981458 (Reactome)
RHOB ProteinP62745 (Uniprot-TrEMBL)
RHOC ProteinP08134 (Uniprot-TrEMBL)
Smooth

muscle/non-muscle

myosin II
ComplexR-HSA-419194 (Reactome) Class 2 myosins are a set of protein complexes that bind actin and hydrolyse ATP, acting as molecular motors. They consist of two myosin heavy chains , two essential light chains and two regulatory light chains (MRLCs). Smooth muscle and non-muscle myosin isoforms are a subset of Class 2 myosin complexes. The nomenclature for isoforms is misleading, as non-muscle isoforms can be found in smooth muscle. The 4 smooth muscle isoforms all have heavy chains encoded by MYH11. The non-muscle isoforms have heavy chains encoded by MYH9, MYH10 or MYH14 (NMHC-IIA, B and C). The essential light chain (LC17) common to smooth and non-muscle isoforms is encoded by MYL6. The regulatory light chain (LC20) is encoded by either MYL9, giving a slightly more basic protein that is referred to as the smooth muscle LC20 isoform, and MRLC2, giving a more acidic isoform referred to as the non-muscle LC20 isoform. Class 2 myosins play a crucial role in a variety of cellular processes, including cell migration, polarity formation, and cytokinesis.
p-T19,S20-MRLC-smooth muscle/non-muscle myosin IIComplexR-HSA-419195 (Reactome) Nonmuscle myosin II (NMM2) is an actin-based motor protein that plays a crucial role in a variety of cellular processes, including smooth muscle contraction, cell migration, polarity formation, and cytokinesis. NMM2 consists of two myosin heavy chains encoded by MYH9, MYH10, MYH14 (NMHC-IIA, B and C) or MYH11, two copies of MYL6 essential light chain protein, and two regulatory light chains (MRLCs), MYL9 and MYL12B. Myosin II activity is stimulated by phosphorylation of MRLC. Diphosphorylation at Thr-19 and Ser-20 (commonly referred in the literature as Thr-18 and Ser-19) increases both actin-activated Mg2+ ATPase activity and the stability of myosin II filaments; monophosphorylation at Ser-20 is less effective (Ikebe and Hartshorne 1985, Ikebe et al. 1988). Kinases responsible for the phosphorylation include myosin light chain kinase (MLCK), ROCK kinase, citron kinase, myotonic dystrophy kinase-related CDC42-binding protein kinase, and Zipper-interacting protein (ZIP) kinase. ROCK activity has been shown to regulate MRLC phosphorylation by directly mono- or diphosphorylating MRLC (Amano et al., 1996, Ueda et al., 2002, Watanabe et al. 2007).
p-T19,S20-MYL12B ProteinO14950 (Uniprot-TrEMBL)
p-T19,S20-MYL9 ProteinP24844 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-5671919 (Reactome)
ATPR-HSA-5671919 (Reactome)
CDKN1BR-HSA-5671972 (Reactome)
CIT-3R-HSA-8981443 (Reactome)
CIT:CDKN1BArrowR-HSA-5671972 (Reactome)
CIT:CDKN1BTBarR-HSA-5625901 (Reactome)
CITR-HSA-5625901 (Reactome)
CITR-HSA-5671972 (Reactome)
DLG4R-HSA-5671993 (Reactome)
KIF14R-HSA-5671970 (Reactome)
Myosin phosphataseTBarR-HSA-5671919 (Reactome)
PRC1R-HSA-5671970 (Reactome)
R-HSA-5625901 (Reactome) Citron kinase CIT was identified as a RHO GTPase effector in a yeast two hybrid screen, where it was shown, using mouse proteins, that CIT strongly binds GTP-bound RHOA, RHOB, RHOC and RAC1, but not CDC42. CIT possesses a centrally located Rho/Rac binding domain, while the kinase domain is located at the N-terminus. CIT is likely a homodimer that is activated by a conformational change upon RHO/RAC1 binding (Madaule et al. 1995).
R-HSA-5671919 (Reactome) Activated CIT phosphorylates MRLCs (mysoin regulatory light chains) at threonine T19 and serine S20 (also labeled in the literature as T18 and S19), and can restore stress fibre assembly when ROCKs are inhibited, although ROCKs play the dominant role in stress fiber formation-related phosphorylation of MRLCs. CIT-mediated phosphorylation of MRLCs may be important during cytokinesis. Unlike ROCKs, CIT does not phosphorylate the myosin binding subunit of the myosin phosphatase complex (Yamashiro et al. 2003).
R-HSA-5671970 (Reactome) Activated citron kinase (CIT) binds KIF14 and PRC1 at the central spindle and mid-body and this evolutionarily conserved interaction is necessary for the formation of the cleavage furrow and completion of cytokinesis. The C-terminal part of the CIT coiled-coil domain binds RHO GTPase while the N-terminal part of the CIT coiled coil domain binds KIF14 (Gruneberg et al. 2006, Watanabe et al. 2013, Bassi et al. 2013).
R-HSA-5671972 (Reactome) The tumor suppressor CDKN1B (p27Kip1) binds CIT (citron kinase) and prevents its association with RHO GTPases. CDKN1B and CIT colocalize at the contractile ring and mid-body of dividing cells and it is thought that CDKN1B controls cytokinesis by regulating CIT activation (Serres et al. 2012).
R-HSA-5671993 (Reactome) CIT-3 (CIT-N, citron-N or citron) is a splicing isoform of CIT that lacks the N-terminal kinase domain. CIT-3 is specifically expressed in the brain, where it participates in the formation of postsynaptic densities at glutamatergic synapses by binding to the postsynaptic density protein PSD-95 (DLG4). Binding of CIT-3 to DLG4 is RHO GTPase-dependent. DLG4 may simultaneously bind CIT-3 and NMDA-type glutamate receptors (Zhang et al. 1999, Furuyashiki et al. 1999, Zhang and Benson 2006).
R-HSA-8981443 (Reactome) The neuronally expressed CIT isoform, CIT-3 (CIT-N), lacks the kinase domain but retains the RHO GTPase binding domain (Di Cunto et al. 1998) and can bind to activated GTP-bound RHOA, RHOB, RHOC and RAC1.
RHOA,RHOB,RHOC,RAC1:GTP:CIT-3:DLG4ArrowR-HSA-5671993 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTP:CIT-3ArrowR-HSA-8981443 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTP:CIT-3R-HSA-5671993 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTP:CIT:KIF14:PRC1ArrowR-HSA-5671970 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTP:CITArrowR-HSA-5625901 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTP:CITR-HSA-5671970 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTP:CITmim-catalysisR-HSA-5671919 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTPR-HSA-5625901 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTPR-HSA-8981443 (Reactome)
Smooth

muscle/non-muscle

myosin II
R-HSA-5671919 (Reactome)
p-T19,S20-MRLC-smooth muscle/non-muscle myosin IIArrowR-HSA-5671919 (Reactome)

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