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Arhgef2  -  rho/rac guanine nucleotide exchange factor...

Mus musculus

Synonyms: AA408978, GEF, GEF-H1, GEFH1, Guanine nucleotide exchange factor H1, ...
 
 
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Disease relevance of Arhgef2

  • Enteropathogenic Escherichia coli activates the RhoA signaling pathway via the stimulation of GEF-H1 [1].
  • The invasion-inducing T-lymphoma invasion and metastasis 1 (Tiam1) protein functions as a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1 [2].
  • The restoration of impaired macrophage functions using as immunomodulator the Corynebacterium granulosum-derived P40 fraction [3].
  • In this paper we describe the effect of the C. granulosum-derived P40 fraction on the growth and metastatization of the transplantable epithelioma T8 of Guèrin [3].
  • Comparative studies have been carried out on the effects on 2 viral-infection models (Herpes virus and influenza virus) of treatments consisting of either C. granulosum-derived immunomodulator P40, or of vidarabin or amantadine as antiviral drugs, or of combinations of vidarabin or amantadine with P40 [4].
 

Psychiatry related information on Arhgef2

  • Both visual and quantitative time studies of the reaction indicated that P40 gave rise to Gz-p30 and Gz-p10 [5].
 

High impact information on Arhgef2

  • The antigen-specific GEF enhanced the antibody response, and antigen-specific GIF suppressed the antibody response, both in carrier specific manner [6].
  • This extension contains the Tyr174 Src-family kinase recognition site, and phosphorylation or truncation of this peptide results in stimulation of GEF activity [7].
  • GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors [8].
  • Autonomous growth and tumorigenicity induced by P40/interleukin 9 cDNA transfection of a mouse P40-dependent T cell line [9].
  • The same P40-dependent cell line transfected with a control construct did not form tumors even after injection of 10(7) cells [9].
 

Biological context of Arhgef2

  • Further, we show that PAK4-mediated phosphorylation of Ser810 acts as a switch to block GEF-H1-dependent stress fiber formation while promoting the formation of lamellipodia in NIH-3T3 cells [10].
  • The inability of cells to assemble a functioning spindle after Lfc inhibition resulted in a delay in mitosis and an accumulation of prometaphase cells [11].
  • These findings demonstrate a role for Lfc, Rho, and mDia1 during mitosis [11].
  • Inhibition of Lfc's primary target Rho GTPase during prophase/prometaphase, or expression of a catalytically inactive mutant of Lfc, also prevented normal spindle assembly and resulted in delays in mitotic progression [11].
  • The transforming cDNA contains a complete open reading frame that encodes a protein (designated Lfc) with a region of sequence similarity to the product of the lbc oncogene [12].
 

Anatomical context of Arhgef2

  • Our observations propose a novel role for PAK4 in GEF-H1-dependent crosstalk between MTs and the actin cytoskeleton [10].
  • A recent study showed that microtubule-bound GEF-H1, a RhoA-specific guanine nucleotide exchange factor, was converted to its active form by microtubule destabilization, and this sequence of events resulted in RhoA stimulation [1].
  • Although the removal of the PH domain of the Lfc protein completely eliminated its ability to transform NIH 3T3 cells, replacement of this domain with an isoprenylation site restored all of its transforming activity [12].
  • In neurons, Lfc was largely found in the shaft of dendrites in association with microtubules but translocated to spines upon neuronal stimulation [13].
  • In summary, we provide the first evidence that the Rho family signaling pathways act as potential regulators of skeletal muscle regeneration and provide the first reported molecular mechanism illustrating how a mammalian Rho family GEF controls this process by modulating mesenchymal cell fate decisions [14].
 

Associations of Arhgef2 with chemical compounds

  • Trio contains two functional guanine nucleotide exchange factors (GEF) domains for the Rho-like GTPases and a serine/threonine kinase domain [15].
  • Vav1 is a guanine nucleotide exchange factor (GEF) for Rho-family GTPases, which is activated by tyrosine phosphorylation following TCR stimulation [16].
  • A factor, termed P40, supporting the growth of these lines was purified and characterized as a basic 32- to 39-kDa single-chain glycoprotein functionally distinct from previously identified T-cell growth factors and apparently unrelated structurally to any known protein [17].
  • The rate of production of the P40 mRNA does not appear to be affected in the dimethyl sulfoxide-treated cells [18].
  • P40 recognized the epitope on the C9b fragment obtained by alpha-thrombin cleavage but did not react with the NH2-terminal or COOH-terminal fragment obtained by trypsin cleavage [19].
 

Physical interactions of Arhgef2

  • Residue His556 of this region, in particular, is important for this activity, since the H556A mutant retained the GEF catalytic capability and the binding activity toward Cdc42 and RhoA in vitro but was deficient in oligomer formation [20].
 

Regulatory relationships of Arhgef2

 

Other interactions of Arhgef2

  • Expression of the first GEF domain alone results in drastically shortened axons and excessive growth cones, mediated by Rac1 [22].
  • We have characterized the DH domain protein mNET1, a Rho-family guanine nucleotide exchange factor (GEF) [23].
  • This interaction modulates both the GEF activity and the targeting to the plasma membrane of onco-Dbl [24].
  • Coordination of the actions of the individual GEF domains through their presence in Kalirin-9, with its Sec14p, spectrin, and Src homology domain 3 motifs, is essential for regulating neurite extension and neuronal morphology [22].
  • Using a recently developed assay for measuring the cellular activation of Rac, we did not find that expression of Lfc increased the levels of GTP-bound Rac1 [21].
 

Analytical, diagnostic and therapeutic context of Arhgef2

  • Examination of the spatial expression patterns of five GEFs in embryos or neonatal brain by in situ hybridization revealed distinct patterns for each GEF [25].
  • In agreement with these observations, immunofluorescence of proliferating MDCK cells revealed that the endogenous canine GEF-H1/Lfc associates with mitotic spindles [26].
  • Gel filtration chromatography revealed that recombinant eIF-2B had the same molecular mass as eIF-2B purified from rat liver and that it did indeed possess GEF activity [27].
  • The role of two residues within the catalytic domain of CDC25Mm, a mouse ras-specific guanine nucleotide exchange factor (GEF), was investigated by site-directed mutagenesis [28].
  • Administration of a single intravenous injection of P40 fraction led to the restoration of all depressed macrophage activities to normal values [3].

References

  1. Enteropathogenic Escherichia coli activates the RhoA signaling pathway via the stimulation of GEF-H1. Matsuzawa, T., Kuwae, A., Yoshida, S., Sasakawa, C., Abe, A. EMBO J. (2004) [Pubmed]
  2. The guanine nucleotide exchange factor Tiam1 affects neuronal morphology; opposing roles for the small GTPases Rac and Rho. Leeuwen, F.N., Kain, H.E., Kammen, R.A., Michiels, F., Kranenburg, O.W., Collard, J.G. J. Cell Biol. (1997) [Pubmed]
  3. The restoration of impaired macrophage functions using as immunomodulator the Corynebacterium granulosum-derived P40 fraction. Mastroeni, P., Bizzini, B., Bonina, L., Iannello, D., Merendino, R.A., Delfino, D., Berlinghieri, M.C., Leonardi, M.S., Arena, A., Liberto, M.C. Immunopharmacology (1985) [Pubmed]
  4. The Corynebacterium granulosum-derived P40 immunomodulator exerts a synergistic effect on the activity of antiviral drugs in the treatment of experimental viral infections. Fattal-German, M., Bizzini, B. Biomed. Pharmacother. (1988) [Pubmed]
  5. Further characterization of the in vitro products generated by proteolytic cleavage of Gazdar murine sarcoma virus p65gag. Maxwell, S.A., Arlinghaus, R.B. J. Gen. Virol. (1985) [Pubmed]
  6. IgE-binding factors and regulation of the IgE antibody response. Ishizaka, K. Annu. Rev. Immunol. (1988) [Pubmed]
  7. Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation. Aghazadeh, B., Lowry, W.E., Huang, X.Y., Rosen, M.K. Cell (2000) [Pubmed]
  8. GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Rossman, K.L., Der, C.J., Sondek, J. Nat. Rev. Mol. Cell Biol. (2005) [Pubmed]
  9. Autonomous growth and tumorigenicity induced by P40/interleukin 9 cDNA transfection of a mouse P40-dependent T cell line. Uyttenhove, C., Druez, C., Renauld, J.C., Hérin, M., Noël, H., Van Snick, J. J. Exp. Med. (1991) [Pubmed]
  10. PAK4 mediates morphological changes through the regulation of GEF-H1. Callow, M.G., Zozulya, S., Gishizky, M.L., Jallal, B., Smeal, T. J. Cell. Sci. (2005) [Pubmed]
  11. The Rho GTP exchange factor Lfc promotes spindle assembly in early mitosis. Bakal, C.J., Finan, D., LaRose, J., Wells, C.D., Gish, G., Kulkarni, S., DeSepulveda, P., Wilde, A., Rottapel, R. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  12. Expression cloning of lfc, a novel oncogene with structural similarities to guanine nucleotide exchange factors and to the regulatory region of protein kinase C. Whitehead, I., Kirk, H., Tognon, C., Trigo-Gonzalez, G., Kay, R. J. Biol. Chem. (1995) [Pubmed]
  13. The Rho-specific GEF Lfc interacts with neurabin and spinophilin to regulate dendritic spine morphology. Ryan, X.P., Alldritt, J., Svenningsson, P., Allen, P.B., Wu, G.Y., Nairn, A.C., Greengard, P. Neuron (2005) [Pubmed]
  14. Modulation of muscle regeneration, myogenesis, and adipogenesis by the Rho family guanine nucleotide exchange factor GEFT. Bryan, B.A., Mitchell, D.C., Zhao, L., Ma, W., Stafford, L.J., Teng, B.B., Liu, M. Mol. Cell. Biol. (2005) [Pubmed]
  15. The two guanine nucleotide exchange factor domains of Trio link the Rac1 and the RhoA pathways in vivo. Bellanger, J.M., Lazaro, J.B., Diriong, S., Fernandez, A., Lamb, N., Debant, A. Oncogene (1998) [Pubmed]
  16. Lineage-specific requirement for the PH domain of Vav1 in the activation of CD4+ but not CD8+ T cells. Prisco, A., Vanes, L., Ruf, S., Trigueros, C., Tybulewicz, V.L. Immunity (2005) [Pubmed]
  17. Functional and structural characterization of P40, a mouse glycoprotein with T-cell growth factor activity. Uyttenhove, C., Simpson, R.J., Van Snick, J. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  18. Regulation of mRNA utilization in mouse erythroleukemia cells induced to differentiate by exposure to dimethyl sulfoxide. Yenofsky, R., Cereghini, S., Krowczynska, A., Brawerman, G. Mol. Cell. Biol. (1983) [Pubmed]
  19. The role of the C9b domain in the binding of C9 molecules to EAC1-8 defined by monoclonal antibodies to C9. Yoden, A., Moriyama, T., Inoue, K., Inai, S. J. Immunol. (1988) [Pubmed]
  20. Oligomerization of DH domain is essential for Dbl-induced transformation. Zhu, K., Debreceni, B., Bi, F., Zheng, Y. Mol. Cell. Biol. (2001) [Pubmed]
  21. The Dbl-related protein, Lfc, localizes to microtubules and mediates the activation of Rac signaling pathways in cells. Glaven, J.A., Whitehead, I., Bagrodia, S., Kay, R., Cerione, R.A. J. Biol. Chem. (1999) [Pubmed]
  22. Distinct roles for the two Rho GDP/GTP exchange factor domains of kalirin in regulation of neurite growth and neuronal morphology. Penzes, P., Johnson, R.C., Kambampati, V., Mains, R.E., Eipper, B.A. J. Neurosci. (2001) [Pubmed]
  23. Activation of RhoA and SAPK/JNK signalling pathways by the RhoA-specific exchange factor mNET1. Alberts, A.S., Treisman, R. EMBO J. (1998) [Pubmed]
  24. Regulation of proto-Dbl by intracellular membrane targeting and protein stability. Vanni, C., Mancini, P., Gao, Y., Ottaviano, C., Guo, F., Salani, B., Torrisi, M.R., Zheng, Y., Eva, A. J. Biol. Chem. (2002) [Pubmed]
  25. Dynamic and coordinated expression profile of dbl-family guanine nucleotide exchange factors in the developing mouse brain. Yoshizawa, M., Sone, M., Matsuo, N., Nagase, T., Ohara, O., Nabeshima, Y., Hoshino, M. Gene Expr. Patterns (2003) [Pubmed]
  26. Identification of a tight junction-associated guanine nucleotide exchange factor that activates Rho and regulates paracellular permeability. Benais-Pont, G., Punn, A., Flores-Maldonado, C., Eckert, J., Raposo, G., Fleming, T.P., Cereijido, M., Balda, M.S., Matter, K. J. Cell Biol. (2003) [Pubmed]
  27. Subunit assembly and guanine nucleotide exchange activity of eukaryotic initiation factor-2B expressed in Sf9 cells. Fabian, J.R., Kimball, S.R., Heinzinger, N.K., Jefferson, L.S. J. Biol. Chem. (1997) [Pubmed]
  28. Mutations at position 1122 in the catalytic domain of the mouse ras-specific guanine nucleotide exchange factor CDC25Mm originate both loss-of-function and gain-of-function proteins. Carrera, V., Moroni, A., Martegani, E., Volponi, C., Cool, R.H., Alberghina, L., Vanoni, M. FEBS Lett. (1998) [Pubmed]
 
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