title: Rnd1 and Rnd3 targeting to lipid raft is required for p190 RhoGAP activation.
abstract: The Rnd proteins Rnd1, Rnd2, and Rnd3/RhoE are well known as key regulators of the actin cytoskeleton in various cell types, but they comprise a distinct subgroup of the Rho family in that they are GTP bound and constitutively active. Functional differences of the Rnd proteins in RhoA inhibition signaling have been reported in various cell types. Rnd1 and Rnd3 antagonize RhoA signaling by activating p190 RhoGAP, whereas Rnd2 does not. However, all the members of the Rnd family have been reported to bind directly to p190 RhoGAP and equally induce activation of p190 RhoGAP in vitro, and there is no evidence that accounts for the functional difference of the Rnd proteins in RhoA inhibition signaling. Here we report the role of the N-terminal region in signaling. Rnd1 and Rnd3, but not Rnd2, have a KERRA (Lys-Glu-Arg-Arg-Ala) sequence of amino acids in their N-terminus, which functions as the lipid raft-targeting determinant. The sequence mediates the lipid raft targeting of p190 RhoGAP correlated with its activation. Overall, our results demonstrate a novel regulatory mechanism by which differential membrane targeting governs activities of Rnd proteins to function as RhoA antagonists.
authors.affiliation: Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. izu-oinuma@lif.kyoto-u.ac.jp
authors.forename: Izumi
authors.initials: I
authors.lastname: Oinuma
authors.forename: Kana
authors.initials: K
authors.lastname: Kawada
authors.forename: Kiyoka
authors.initials: K
authors.lastname: Tsukagoshi
authors.forename: Manabu
authors.initials: M
authors.lastname: Negishi
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D021962:Membrane Microdomains / Q000502:physiology*; D051379:Mice; D011485:Protein Binding; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: C074560:ARHGAP35 protein, human; D020662:Guanine Nucleotide Exchange Factors; C491772:RND1 protein, human; D012097:Repressor Proteins; C508704:RND2 protein, human; C508705:RND3 protein, human; D020741:rho GTP-Binding Proteins