RHO GTPases Activate Rhotekin and Rhophilins (Homo sapiens)

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Rhotekin (RTKN) is a protein with an N-terminally located RHO GTPase binding domain, that shares a limited sequence homology with PKNs and rhophilins. RTKN binds to GTP-bound RHOA, RHOB and RHOC and can inhibit their GTPase activity (Reid et al. 1996, Fu et al. 2000), which can be corroborated by protein kinase D-mediated phosphorylation of RTKN (Pusapati et al. 2012). RTKN is implicated in the establishment of cell polarity (Sudo et al. 2006), septin organization (Ito et al. 2005, Sudo et al. 2007) and stimulation of SRF-mediated transcription (Reynaud et al. 2000). RTKN can have an anti-apoptotic effect that depends on the activation of NFKB (NF-kappaB) (Liu et al. 2004). RTKN2 (rhotekin-2) is another rhotekin exclusively expressed in lymphocytes (Collier et al. 2004). The function and the mechanism of action of RTKN2 are unknown.

Rhophillins include two family members - rhophilin-1 (RHNP1) and rhophilin-2 (RHPN2) with ~75% sequence identity. A RHO GTPase binding domain is located at the N-terminus of rhophilins, followed by a BRO1 domain (characteristic of proteins involved in protein kinase C signaling) and a C-terminal PDZ domain. RHOA:GTP binds both RHPN1 and RHPN2 and these interactions may be involved in organization of the actin cytoskeleton and/or cell motility (Watanabe et al. 1996, Fujita et al. 2000, Peck et al. 2002). RHOB:GTP recruits RHPN2 to endosomes which may be involved in the function of thyroid cells (Mircescu et al. 2002). View original pathway at:Reactome.</div>


Pathway is converted from Reactome ID: 5666185
Reactome version: 66
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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  1. Mircescu H, Steuve S, Savonet V, Degraef C, Mellor H, Dumont JE, Maenhaut C, Pirson I.; ''Identification and characterization of a novel activated RhoB binding protein containing a PDZ domain whose expression is specifically modulated in thyroid cells by cAMP.''; PubMed
  2. Watanabe G, Saito Y, Madaule P, Ishizaki T, Fujisawa K, Morii N, Mukai H, Ono Y, Kakizuka A, Narumiya S.; ''Protein kinase N (PKN) and PKN-related protein rhophilin as targets of small GTPase Rho.''; PubMed
  3. Behrends J, Clément S, Pajak B, Pohl V, Maenhaut C, Dumont JE, Schurmans S.; ''Normal thyroid structure and function in rhophilin 2-deficient mice.''; PubMed
  4. Collier FM, Gregorio-King CC, Gough TJ, Talbot CD, Walder K, Kirkland MA.; ''Identification and characterization of a lymphocytic Rho-GTPase effector: rhotekin-2.''; PubMed
  5. Reid T, Furuyashiki T, Ishizaki T, Watanabe G, Watanabe N, Fujisawa K, Morii N, Madaule P, Narumiya S.; ''Rhotekin, a new putative target for Rho bearing homology to a serine/threonine kinase, PKN, and rhophilin in the rho-binding domain.''; PubMed
  6. Ito H, Iwamoto I, Morishita R, Nozawa Y, Narumiya S, Asano T, Nagata K.; ''Possible role of Rho/Rhotekin signaling in mammalian septin organization.''; PubMed
  7. Sudo K, Ito H, Iwamoto I, Morishita R, Asano T, Nagata K.; ''Identification of a cell polarity-related protein, Lin-7B, as a binding partner for a Rho effector, Rhotekin, and their possible interaction in neurons.''; PubMed
  8. Reynaud C, Fabre S, Jalinot P.; ''The PDZ protein TIP-1 interacts with the Rho effector rhotekin and is involved in Rho signaling to the serum response element.''; PubMed
  9. Fujita A, Nakamura K, Kato T, Watanabe N, Ishizaki T, Kimura K, Mizoguchi A, Narumiya S.; ''Ropporin, a sperm-specific binding protein of rhophilin, that is localized in the fibrous sheath of sperm flagella.''; PubMed
  10. Pusapati GV, Eiseler T, Rykx A, Vandoninck S, Derua R, Waelkens E, Van Lint J, von Wichert G, Seufferlein T.; ''Protein kinase D regulates RhoA activity via rhotekin phosphorylation.''; PubMed
  11. Peck JW, Oberst M, Bouker KB, Bowden E, Burbelo PD.; ''The RhoA-binding protein, rhophilin-2, regulates actin cytoskeleton organization.''; PubMed
  12. Liu CA, Wang MJ, Chi CW, Wu CW, Chen JY.; ''Rho/Rhotekin-mediated NF-kappaB activation confers resistance to apoptosis.''; PubMed
  13. Sudo K, Ito H, Iwamoto I, Morishita R, Asano T, Nagata K.; ''SEPT9 sequence alternations causing hereditary neuralgic amyotrophy are associated with altered interactions with SEPT4/SEPT11 and resistance to Rho/Rhotekin-signaling.''; PubMed
  14. Fu Q, Yu L, Liu Q, Zhang J, Zhang H, Zhao S.; ''Molecular cloning, expression characterization, and mapping of a novel putative inhibitor of rho GTPase activity, RTKN, to D2S145-D2S286.''; PubMed


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93630view11:29, 9 August 2017ReactomeTeamreactome version 61
89088view08:04, 22 August 2016EgonwOntology Term : 'signaling pathway' added !
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83383view11:04, 18 November 2015ReactomeTeamVersion54
81561view13:06, 21 August 2015ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
GTP MetaboliteCHEBI:15996 (ChEBI)
LIN7B ProteinQ9HAP6 (Uniprot-TrEMBL)
LIN7BProteinQ9HAP6 (Uniprot-TrEMBL)
RHOA ProteinP61586 (Uniprot-TrEMBL)
RHOA,B,C:GTP:RTKNComplexR-HSA-5666177 (Reactome)
RHOA/B/C:GTPComplexR-HSA-419161 (Reactome)
RHOA:GTP:RHPN1,RHPN2ComplexR-HSA-5667010 (Reactome)
RHOA:GTP:RHPN1:ROPN1ComplexR-HSA-5667059 (Reactome)
RHOA:GTP:RHPN1ComplexR-HSA-5667060 (Reactome)
RHOA:GTP:RTKN:LIN7BComplexR-HSA-5666198 (Reactome)
RHOA:GTP:RTKN:TAX1BP3ComplexR-HSA-5666210 (Reactome)
RHOA:GTP:RTKNComplexR-HSA-5666199 (Reactome)
RHOA:GTPComplexR-HSA-5665993 (Reactome)
RHOB ProteinP62745 (Uniprot-TrEMBL)
RHOB:GTP:RHPN2ComplexR-HSA-5667030 (Reactome)
RHOB:GTPComplexR-HSA-5666081 (Reactome)
RHOC ProteinP08134 (Uniprot-TrEMBL)
RHPN1 ProteinQ8TCX5 (Uniprot-TrEMBL)
RHPN1,RHPN2ComplexR-HSA-5667005 (Reactome)
RHPN2 ProteinQ8IUC4 (Uniprot-TrEMBL)
RHPN2ProteinQ8IUC4 (Uniprot-TrEMBL)
ROPN1 ProteinQ9HAT0 (Uniprot-TrEMBL)
ROPN1ComplexR-HSA-5667061 (Reactome)
RTKN ProteinQ9BST9 (Uniprot-TrEMBL)
RTKNProteinQ9BST9 (Uniprot-TrEMBL)
TAX1BP3 ProteinO14907 (Uniprot-TrEMBL)
TAX1BP3ProteinO14907 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
LIN7BR-HSA-5666197 (Reactome)
R-HSA-5666178 (Reactome) Rhotekin (RTKN) has the evolutionarily conserved RHO GTPase binding domain at its N-terminus and strongly binds to RHOA and RHOC. RTKN also associates with RHOB with a lower affinity and does not bind RAC1 or CDC42 (Reid et al. 1996). Binding of RTKN may inhibit the GTPase activity of RHO GTPases (Fu et al. 2000).
R-HSA-5666197 (Reactome) RTKN (rhotekin) associated with activated RHOA (RHOA:GTP) binds LIN7B, a cell polarity-related protein. Both LIN7B and RTKN are highly expressed in neurons (Sudo et al. 2006).
R-HSA-5666216 (Reactome) The PDZ domain of TAX1BP3 (TIP-1) binds the C-terminus of RTKN (rhotekin) associated with activated RHOA (RHOA:GTP). Binding of TAX1BP3 to the RHOA:GTP:RTKN complex stimulates SRF-mediated transcription through an unknown mechanism (Reynaud et al. 2000).
R-HSA-5667008 (Reactome) Activated RHOA (RHOA:GTP) binds rhophilin-1 (RHPN1) or rophilin-2 (RHPN2). RHPN1 and RHPN2 share 75% sequence identity, with the RHO-binding domain at the N-terminus, followed by the BRO1 domain in their central region (characteristic of proteins involved in protein kinase C signaling), and the PDZ domain in the C-terminal region. PDZ domains of RHPN1 and RHPN2 exhibit little homology (Watanabe et al. 1996, Peck et al. 2002). RHPN2 may be involved in the regulation of the actin cytoskeleton organization downstream of RHOA (Peck et al. 2002).
R-HSA-5667037 (Reactome) RHPN2 (rhophilin-2) binds to activated RHOB (RHOB:GTP) and relocalizes to endosomal membrane. The expression of the mouse Rhpn2 in thyrocytes increases upon TSH stimulation (Mircescu et al. 2002). This implied an important function of Rhpn2 in the thyroid, but Rhpn2 deficient mice exhibit normal thyroid structure and function, as well as an overall normal development (Behrends et al. 2005).
R-HSA-5667052 (Reactome) Ropporin (ROPN1), a protein specific to spermatozoid tails, binds rhophilin-1 (RHPN1) associated with activated RHOA (RHOA:GTP) (Fujita et al. 2000).
RHOA,B,C:GTP:RTKNArrowR-HSA-5666178 (Reactome)
RHOA/B/C:GTPR-HSA-5666178 (Reactome)
RHOA:GTP:RHPN1,RHPN2ArrowR-HSA-5667008 (Reactome)
RHOA:GTP:RHPN1:ROPN1ArrowR-HSA-5667052 (Reactome)
RHOA:GTP:RHPN1R-HSA-5667052 (Reactome)
RHOA:GTP:RTKN:LIN7BArrowR-HSA-5666197 (Reactome)
RHOA:GTP:RTKN:TAX1BP3ArrowR-HSA-5666216 (Reactome)
RHOA:GTP:RTKNR-HSA-5666197 (Reactome)
RHOA:GTP:RTKNR-HSA-5666216 (Reactome)
RHOA:GTPR-HSA-5667008 (Reactome)
RHOB:GTP:RHPN2ArrowR-HSA-5667037 (Reactome)
RHOB:GTPR-HSA-5667037 (Reactome)
RHPN1,RHPN2R-HSA-5667008 (Reactome)
RHPN2R-HSA-5667037 (Reactome)
ROPN1R-HSA-5667052 (Reactome)
RTKNR-HSA-5666178 (Reactome)
TAX1BP3R-HSA-5666216 (Reactome)

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