RHO GTPases Activate Rhotekin and Rhophilins

Stable Identifier
R-HSA-5666185
Type
Pathway
Species
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).

Literature References
PubMed ID Title Journal Year
17546647 SEPT9 sequence alternations causing hereditary neuralgic amyotrophy are associated with altered interactions with SEPT4/SEPT11 and resistance to Rho/Rhotekin-signaling

Sudo, K, Ito, H, Iwamoto, I, Morishita, R, Asano, T, Nagata, K

Hum. Mutat. 2007
12221077 The RhoA-binding protein, rhophilin-2, regulates actin cytoskeleton organization

Peck, JW, Oberst, M, Bouker, KB, Bowden, E, Burbelo, PD

J. Biol. Chem. 2002
10940294 The PDZ protein TIP-1 interacts with the Rho effector rhotekin and is involved in Rho signaling to the serum response element

Reynaud, C, Fabre, S, Jalinot, P

J. Biol. Chem. 2000
8662891 Rhotekin, a new putative target for Rho bearing homology to a serine/threonine kinase, PKN, and rhophilin in the rho-binding domain

Reid, T, Furuyashiki, T, Ishizaki, T, Watanabe, G, Watanabe, N, Fujisawa, K, Morii, N, Madaule, P, Narumiya, S

J. Biol. Chem. 1996
8571126 Protein kinase N (PKN) and PKN-related protein rhophilin as targets of small GTPase Rho

Watanabe, G, Saito, Y, Madaule, P, Ishizaki, T, Fujisawa, K, Morii, N, Mukai, H, Ono, Y, Kakizuka, A, Narumiya, S

Science 1996
22228765 Protein kinase D regulates RhoA activity via rhotekin phosphorylation

Pusapati, GV, Eiseler, T, Rykx, A, Vandoninck, S, Derua, R, Waelkens, E, Van Lint, J, von Wichert, G, Seufferlein, T

J. Biol. Chem. 2012
15480428 Rho/Rhotekin-mediated NF-kappaB activation confers resistance to apoptosis

Liu, CA, Wang, MJ, Chi, CW, Wu, CW, Chen, JY

Oncogene 2004
16979770 Identification of a cell polarity-related protein, Lin-7B, as a binding partner for a Rho effector, Rhotekin, and their possible interaction in neurons

Sudo, K, Ito, H, Iwamoto, I, Morishita, R, Asano, T, Nagata, K

Neurosci. Res. 2006
12473120 Identification and characterization of a novel activated RhoB binding protein containing a PDZ domain whose expression is specifically modulated in thyroid cells by cAMP

Mircescu, H, Steuve, S, Savonet, V, Degraef, C, Mellor, H, Dumont, JE, Maenhaut, C, Pirson, I

Eur. J. Biochem. 2002
10873388 Molecular cloning, expression characterization, and mapping of a novel putative inhibitor of rho GTPase activity, RTKN, to D2S145-D2S286

Fu, Q, Yu, L, Liu, Q, Zhang, J, Zhang, H, Zhao, S

Genomics 2000
15504364 Identification and characterization of a lymphocytic Rho-GTPase effector: rhotekin-2

Collier, FM, Gregorio-King, CC, Gough, TJ, Talbot, CD, Walder, K, Kirkland, MA

Biochem. Biophys. Res. Commun. 2004
16007136 Possible role of Rho/Rhotekin signaling in mammalian septin organization

Ito, H, Iwamoto, I, Morishita, R, Nozawa, Y, Narumiya, S, Asano, T, Nagata, K

Oncogene 2005
10591629 Ropporin, a sperm-specific binding protein of rhophilin, that is localized in the fibrous sheath of sperm flagella

Fujita, A, Nakamura, K, Kato, T, Watanabe, N, Ishizaki, T, Kimura, K, Mizoguchi, A, Narumiya, S

J. Cell. Sci. 2000
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