G-protein signaling - RhoB regulation pathway

RhoB regulation pathway

Ras homolog gene family, member A (RhoB) is a member of a family of small GTPases. Rho GTPases control multiple cellular processes, including actin and microtubule dynamics, gene expression, the cell cycle, cell polarity and membrane transport through their ability to bind to numerous downstream effectors that lead to diverse parallel downstream signaling pathways 7749321[1], [2].

There are several classes of regulatory proteins that affect the activation state of RhoB. Guanine nucleotide exchange factors (GEFs) promote exchange of GTP for GDP, thereby activate Rho proteins. Rho/rac guanine nucleotide exchange factor (GEF) 2 (ARHGEF2) and Rho guanine nucleotide exchange factor (GEF) 3 (ARHGEF3) are known GEFs for RhoB [3], [4]. Vav 2 guanine nucleotide exchange factor (VAV-2) and Rho guanine nucleotide exchange factor (GEF) 10-like (GrinchGEF) also can stimulate activity of RhoB [5], [6].

Geranylgeranyltransferase type I (GGTase-I) and Farnesyltransferase CAAX box (FTase) promote post-translational modification of RhoB protein by geranylgeranylation and farnesylation. It is also essential for RhoB biological activity [7], [8].

Guaninenucleotide-dissociation inhibitors (GDIs) bind to prenylated GDP-bound Rho proteins and allow translocation between membranes and the cytosol [2]. The most known RhoB GDIs are Rho GDP dissociation inhibitors (GDI) alpha and gamma (RhoGDI alpha and RhoGDI gamma). They bind to RhoB and suppress its activation [9], [10].

Once activated, the GTPases bind to a spectrum of effectors to stimulate downstream signaling pathways. RhoB binding to key effectors Diaphanous homolog 1, 3 (DIA1, mDIA2(DIAPH3)) and Rhophilin Rho GTPase binding protein 2 (Rhophilin 2) leads to actin polymerization and cytoskeleton rearrangements and also regulates endosomal trafficking [11], [12], [13]. Protein kinase N1 (PRK1) and Rhotekin are also well-known RhoB downstream effectors [14], [15]. And finally, RhoB can directly bind to Phospholipase C epsilon 1 (PLC-epsilon 1) and stimulate its enzymatic activity [16], [17].

References:

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   XPLN, a guanine nucleotide exchange factor for RhoA and RhoB, but not RhoC. The Journal of biological chemistry 2002 Nov 8;277(45):42964-72
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   TRIF-GEFH1-RhoB pathway is involved in MHCII expression on dendritic cells that is critical for CD4 T-cell activation. The EMBO journal 2006 Sep 6;25(17):4108-19
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   GrinchGEF--a novel Rho-specific guanine nucleotide exchange factor. Biochemical and biophysical research communications 2005 Oct 7;335(4):1280-6
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   Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB. The Journal of biological chemistry 1997 Jun 20;272(25):15591-4
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11. 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. European journal of biochemistry / FEBS 2002 Dec;269(24):6241-9
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14. 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. The Journal of biological chemistry 1996 Jun 7;271(23):13556-60
15. Gampel A, Parker PJ, Mellor H
    Regulation of epidermal growth factor receptor traffic by the small GTPase rhoB. Current biology : CB 1999 Sep 9;9(17):955-8
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    Direct activation of phospholipase C-epsilon by Rho. The Journal of biological chemistry 2003 Oct 17;278(42):41253-8
17. Bunney TD, Katan M
    Phospholipase C epsilon: linking second messengers and small GTPases. Trends in cell biology 2006 Dec;16(12):640-8