G-protein signaling - Rap1B regulation pathway

Rap1B regulation pathway

RAP1B member of RAS oncogene family (Rap-1B) is a member of the Ras-like small GTPases family. It is activated by many extracellular stimuli and is strongly implicated in the control of integrin-mediated cell adhesion [1], [2], [3], [4].

Rap-1B is posttranslationally modified by geranylgeranylation of cysteine 181 residue, catalyzed by Geranylgeranyltransferase type I (GGTase-I) [5]. Geranylgeranylated Rap-1B undergoes RCE1 homolog prenyl protein peptidase (CAAX prenyl protease 2)-dependent processing [6].

Activity of Rap-1B is mainly regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs and GAPs promote GTP (active) and GDP (inactive) state of Rap-1B, respectively [3].

RAP1 GTP-GDP dissociation stimulator 1 (RAP1GDS1) and Rap guanine nucleotide exchange factor 1 (C3G) are known GEFs for Rap-1B [4]. Kinesin-associated protein 3 (KAP3) binds to RAP1GDS1 and stimulates its activity [7]. C3G activity is stimulated by Growth factor receptor-bound protein 2 (GRB2) [8]. Activated RAP1GDS1 and C3G are capable to stimulate GDP/GDP exchange and to activate Rap-1B [4], [9].

Tuberous sclerosis 2 (Tuberin) and RAS p21 protein activator 3 (RASA3) exhibit GAP activity towards Rap-1B and inactivate it [4], [10], [11], [12].

Protein kinase cAMP-dependent catalytic (PKA-cat (cAMP-dependent)) stimulated by cAMP is capable to phosphorylate and activate Rap-1B and this stimulates Rap-1B association with ATPase Ca⁺⁺ transporting ubiquitous (Ca-ATPase3) [13], [14], [15].

References:

1. Knox AL, Brown NH
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   The role of Rap1 in integrin-mediated cell adhesion. Biochemical Society transactions 2003 Feb;31(Pt 1):83-6
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   Rap1 GTPase: functions, regulation, and malignancy. Journal of biochemistry 2003 Oct;134(4):479-84
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   Posttranslationally processed structure of the human platelet protein smg p21B: evidence for geranylgeranylation and carboxyl methylation of the C-terminal cysteine. Proceedings of the National Academy of Sciences of the United States of America 1990 Nov;87(22):8960-4
6. Kim E, Ambroziak P, Otto JC, Taylor B, Ashby M, Shannon K, Casey PJ, Young SG
   Disruption of the mouse Rce1 gene results in defective Ras processing and mislocalization of Ras within cells. The Journal of biological chemistry 1999 Mar 26;274(13):8383-90
7. Shimizu K, Kawabe H, Minami S, Honda T, Takaishi K, Shirataki H, Takai Y
   SMAP, an Smg GDS-associating protein having arm repeats and phosphorylated by Src tyrosine kinase. The Journal of biological chemistry 1996 Oct 25;271(43):27013-7
8. Tanaka S, Morishita T, Hashimoto Y, Hattori S, Nakamura S, Shibuya M, Matuoka K, Takenawa T, Kurata T, Nagashima K
   C3G, a guanine nucleotide-releasing protein expressed ubiquitously, binds to the Src homology 3 domains of CRK and GRB2/ASH proteins. Proceedings of the National Academy of Sciences of the United States of America 1994 Apr 12;91(8):3443-7
9. Gotoh T, Hattori S, Nakamura S, Kitayama H, Noda M, Takai Y, Kaibuchi K, Matsui H, Hatase O, Takahashi H
   Identification of Rap1 as a target for the Crk SH3 domain-binding guanine nucleotide-releasing factor C3G. Molecular and cellular biology 1995 Dec;15(12):6746-53
10. Wienecke R, Maize JC Jr, Shoarinejad F, Vass WC, Reed J, Bonifacino JS, Resau JH, de Gunzburg J, Yeung RS, DeClue JE
    Co-localization of the TSC2 product tuberin with its target Rap1 in the Golgi apparatus. Oncogene 1996 Sep 5;13(5):913-23
11. Woods SA, Marmor E, Feldkamp M, Lau N, Apicelli AJ, Boss G, Gutmann DH, Guha A
    Aberrant G protein signaling in nervous system tumors. Journal of neurosurgery 2002 Sep;97(3):627-42
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    GAP1 family members constitute bifunctional Ras and Rap GTPase-activating proteins. The Journal of biological chemistry 2006 Apr 14;281(15):9891-900
13. Altschuler DL, Peterson SN, Ostrowski MC, Lapetina EG
    Cyclic AMP-dependent activation of Rap1b. The Journal of biological chemistry 1995 May 5;270(18):10373-6
14. Lacabaratz-Porret C, Corvazier E, Kovacs T, Bobe R, Bredoux R, Launay S, Papp B, Enouf J
    Platelet sarco/endoplasmic reticulum Ca2+ATPase isoform 3b and Rap 1b: interrelation and regulation in physiopathology. The Biochemical journal 1998 May 15;332 ( Pt 1):173-81
15. Lou L, Urbani J, Ribeiro-Neto F, Altschuler DL
    cAMP inhibition of Akt is mediated by activated and phosphorylated Rap1b. The Journal of biological chemistry 2002 Sep 6;277(36):32799-806