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EMBO J. Jul 15, 1998; 17(14): 4075–4085.
PMCID: PMC1170740

Activation of RhoA and SAPK/JNK signalling pathways by the RhoA-specific exchange factor mNET1.

Abstract

We have characterized the DH domain protein mNET1, a Rho-family guanine nucleotide exchange factor (GEF). N-terminal truncation of mNET1 generates an activated transforming form of the protein, mNET1DeltaN, which acts as a GEF for RhoA but not Cdc42 or Rac1. In NIH 3T3 cells, activated mNET1 induces formation of actin stress fibres and potentiates activity of the transcription factor serum response factor. Inhibitor studies show that these processes are dependent on RhoA and independent of Cdc42 or Rac1. In contrast to the GTPase-deficient RhoA.V14 mutant, however, expression of activated mNET1 also activates the SAPK/JNK pathway. This requires mNET1 GEF activity, since it is blocked by point mutations in the mNET1 DH domain and its C-terminal pleckstrin homology (PH) domain, and by the dominant-interfering RhoA mutant RhoA.N19. Although mNET1DeltaN-induced SAPK/JNK activation requires a C3 transferase-sensitive GTPase, it occurs independently of the generation of titratable GTP-bound RhoA. Thus, mNET1 can activate signalling pathways in addition to those directly controlled by activated RhoA.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Alberts AS, Frost JA, Thorburn AM. Rapid transcriptional assay for the expression of two distinct reporter genes by microinjection. DNA Cell Biol. 1993 Dec;12(10):935–943. [PubMed]
  • Alberts AS, Geneste O, Treisman R. Activation of SRF-regulated chromosomal templates by Rho-family GTPases requires a signal that also induces H4 hyperacetylation. Cell. 1998 Feb 20;92(4):475–487. [PubMed]
  • Alberts AS, Bouquin N, Johnston LH, Treisman R. Analysis of RhoA-binding proteins reveals an interaction domain conserved in heterotrimeric G protein beta subunits and the yeast response regulator protein Skn7. J Biol Chem. 1998 Apr 10;273(15):8616–8622. [PubMed]
  • Antonyak MA, Moscatello DK, Wong AJ. Constitutive activation of c-Jun N-terminal kinase by a mutant epidermal growth factor receptor. J Biol Chem. 1998 Jan 30;273(5):2817–2822. [PubMed]
  • Cerione RA, Zheng Y. The Dbl family of oncogenes. Curr Opin Cell Biol. 1996 Apr;8(2):216–222. [PubMed]
  • Chan AM, Takai S, Yamada K, Miki T. Isolation of a novel oncogene, NET1, from neuroepithelioma cells by expression cDNA cloning. Oncogene. 1996 Mar 21;12(6):1259–1266. [PubMed]
  • Clark GJ, Westwick JK, Der CJ. p120 GAP modulates Ras activation of Jun kinases and transformation. J Biol Chem. 1997 Jan 17;272(3):1677–1681. [PubMed]
  • Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N, Miki T, Gutkind JS. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell. 1995 Jun 30;81(7):1137–1146. [PubMed]
  • Debant A, Serra-Pagès C, Seipel K, O'Brien S, Tang M, Park SH, Streuli M. The multidomain protein Trio binds the LAR transmembrane tyrosine phosphatase, contains a protein kinase domain, and has separate rac-specific and rho-specific guanine nucleotide exchange factor domains. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5466–5471. [PMC free article] [PubMed]
  • Feig LA, Cooper GM. Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP. Mol Cell Biol. 1988 Aug;8(8):3235–3243. [PMC free article] [PubMed]
  • Feng DF, Doolittle RF. Progressive sequence alignment as a prerequisite to correct phylogenetic trees. J Mol Evol. 1987;25(4):351–360. [PubMed]
  • Glaven JA, Whitehead IP, Nomanbhoy T, Kay R, Cerione RA. Lfc and Lsc oncoproteins represent two new guanine nucleotide exchange factors for the Rho GTP-binding protein. J Biol Chem. 1996 Nov 1;271(44):27374–27381. [PubMed]
  • Hart MJ, Eva A, Zangrilli D, Aaronson SA, Evans T, Cerione RA, Zheng Y. Cellular transformation and guanine nucleotide exchange activity are catalyzed by a common domain on the dbl oncogene product. J Biol Chem. 1994 Jan 7;269(1):62–65. [PubMed]
  • Hill CS, Wynne J, Treisman R. The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF. Cell. 1995 Jun 30;81(7):1159–1170. [PubMed]
  • Horii Y, Beeler JF, Sakaguchi K, Tachibana M, Miki T. A novel oncogene, ost, encodes a guanine nucleotide exchange factor that potentially links Rho and Rac signaling pathways. EMBO J. 1994 Oct 17;13(20):4776–4786. [PMC free article] [PubMed]
  • Khosravi-Far R, Solski PA, Clark GJ, Kinch MS, Der CJ. Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation. Mol Cell Biol. 1995 Nov;15(11):6443–6453. [PMC free article] [PubMed]
  • Lebowitz PF, Du W, Prendergast GC. Prenylation of RhoB is required for its cell transforming function but not its ability to activate serum response element-dependent transcription. J Biol Chem. 1997 Jun 27;272(26):16093–16095. [PubMed]
  • Lim L, Manser E, Leung T, Hall C. Regulation of phosphorylation pathways by p21 GTPases. The p21 Ras-related Rho subfamily and its role in phosphorylation signalling pathways. Eur J Biochem. 1996 Dec 1;242(2):171–185. [PubMed]
  • Lin R, Bagrodia S, Cerione R, Manor D. A novel Cdc42Hs mutant induces cellular transformation. Curr Biol. 1997 Oct 1;7(10):794–797. [PubMed]
  • Minden A, Lin A, Claret FX, Abo A, Karin M. Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Cell. 1995 Jun 30;81(7):1147–1157. [PubMed]
  • Mohun T, Garrett N, Treisman R. Xenopus cytoskeletal actin and human c-fos gene promoters share a conserved protein-binding site. EMBO J. 1987 Mar;6(3):667–673. [PMC free article] [PubMed]
  • Moscow JA, He R, Gnarra JR, Knutsen T, Weng Y, Zhao WP, Whang-Peng J, Linehan WM, Cowan KH. Examination of human tumors for rhoA mutations. Oncogene. 1994 Jan;9(1):189–194. [PubMed]
  • Olson MF, Ashworth A, Hall A. An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1. Science. 1995 Sep 1;269(5228):1270–1272. [PubMed]
  • Olson MF, Pasteris NG, Gorski JL, Hall A. Faciogenital dysplasia protein (FGD1) and Vav, two related proteins required for normal embryonic development, are upstream regulators of Rho GTPases. Curr Biol. 1996 Dec 1;6(12):1628–1633. [PubMed]
  • Perona R, Esteve P, Jiménez B, Ballestero RP, Ramón y Cajal S, Lacal JC. Tumorigenic activity of rho genes from Aplysia californica. Oncogene. 1993 May;8(5):1285–1292. [PubMed]
  • Perona R, Montaner S, Saniger L, Sánchez-Pérez I, Bravo R, Lacal JC. Activation of the nuclear factor-kappaB by Rho, CDC42, and Rac-1 proteins. Genes Dev. 1997 Feb 15;11(4):463–475. [PubMed]
  • Prendergast GC, Khosravi-Far R, Solski PA, Kurzawa H, Lebowitz PF, Der CJ. Critical role of Rho in cell transformation by oncogenic Ras. Oncogene. 1995 Jun 15;10(12):2289–2296. [PubMed]
  • Price MA, Rogers AE, Treisman R. Comparative analysis of the ternary complex factors Elk-1, SAP-1a and SAP-2 (ERP/NET). EMBO J. 1995 Jun 1;14(11):2589–2601. [PMC free article] [PubMed]
  • Qiu RG, Chen J, Kirn D, McCormick F, Symons M. An essential role for Rac in Ras transformation. Nature. 1995 Mar 30;374(6521):457–459. [PubMed]
  • Qiu RG, Chen J, McCormick F, Symons M. A role for Rho in Ras transformation. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11781–11785. [PMC free article] [PubMed]
  • Qiu RG, Abo A, McCormick F, Symons M. Cdc42 regulates anchorage-independent growth and is necessary for Ras transformation. Mol Cell Biol. 1997 Jun;17(6):3449–3458. [PMC free article] [PubMed]
  • Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell. 1992 Aug 7;70(3):401–410. [PubMed]
  • Rodrigues GA, Park M, Schlessinger J. Activation of the JNK pathway is essential for transformation by the Met oncogene. EMBO J. 1997 May 15;16(10):2634–2645. [PMC free article] [PubMed]
  • Sahai E, Alberts AS, Treisman R. RhoA effector mutants reveal distinct effector pathways for cytoskeletal reorganization, SRF activation and transformation. EMBO J. 1998 Mar 2;17(5):1350–1361. [PMC free article] [PubMed]
  • Sánchez I, Hughes RT, Mayer BJ, Yee K, Woodgett JR, Avruch J, Kyriakis JM, Zon LI. Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun. Nature. 1994 Dec 22;372(6508):794–798. [PubMed]
  • Teramoto H, Crespo P, Coso OA, Igishi T, Xu N, Gutkind JS. The small GTP-binding protein rho activates c-Jun N-terminal kinases/stress-activated protein kinases in human kidney 293T cells. Evidence for a Pak-independent signaling pathway. J Biol Chem. 1996 Oct 18;271(42):25731–25734. [PubMed]
  • Toksoz D, Williams DA. Novel human oncogene lbc detected by transfection with distinct homology regions to signal transduction products. Oncogene. 1994 Feb;9(2):621–628. [PubMed]
  • Van Aelst L, D'Souza-Schorey C. Rho GTPases and signaling networks. Genes Dev. 1997 Sep 15;11(18):2295–2322. [PubMed]
  • van Leeuwen FN, van der Kammen RA, Habets GG, Collard JG. Oncogenic activity of Tiam1 and Rac1 in NIH3T3 cells. Oncogene. 1995 Dec 7;11(11):2215–2221. [PubMed]
  • Whitehead I, Kirk H, Kay R. Retroviral transduction and oncogenic selection of a cDNA encoding Dbs, a homolog of the Dbl guanine nucleotide exchange factor. Oncogene. 1995 Feb 16;10(4):713–721. [PubMed]
  • Whitehead I, Kirk H, Tognon C, Trigo-Gonzalez G, Kay R. Expression cloning of lfc, a novel oncogene with structural similarities to guanine nucleotide exchange factors and to the regulatory region of protein kinase C. J Biol Chem. 1995 Aug 4;270(31):18388–18395. [PubMed]
  • Whitehead IP, Khosravi-Far R, Kirk H, Trigo-Gonzalez G, Der CJ, Kay R. Expression cloning of lsc, a novel oncogene with structural similarities to the Dbl family of guanine nucleotide exchange factors. J Biol Chem. 1996 Aug 2;271(31):18643–18650. [PubMed]
  • Whitehead IP, Campbell S, Rossman KL, Der CJ. Dbl family proteins. Biochim Biophys Acta. 1997 Feb 22;1332(1):F1–23. [PubMed]
  • Zhang S, Han J, Sells MA, Chernoff J, Knaus UG, Ulevitch RJ, Bokoch GM. Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak1. J Biol Chem. 1995 Oct 13;270(41):23934–23936. [PubMed]
  • Zheng Y, Bender A, Cerione RA. Interactions among proteins involved in bud-site selection and bud-site assembly in Saccharomyces cerevisiae. J Biol Chem. 1995 Jan 13;270(2):626–630. [PubMed]
  • Zheng Y, Hart MJ, Cerione RA. Guanine nucleotide exchange catalyzed by dbl oncogene product. Methods Enzymol. 1995;256:77–84. [PubMed]
  • Zheng Y, Olson MF, Hall A, Cerione RA, Toksoz D. Direct involvement of the small GTP-binding protein Rho in lbc oncogene function. J Biol Chem. 1995 Apr 21;270(16):9031–9034. [PubMed]

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