Pathway maps

G-protein signaling_Rap1A regulation pathway
G-protein signaling_Rap1A regulation pathway

Object List (links open in MetaCore):

1-(1,2-diacyl-glycerol 3-phospho)-inositol 4-phosphate, G-protein alpha-i family, cAMP-GEFII, cAMP-GEFI, Krit1, RASA3, PDZ-GEF1, 3.1.4.11, Tuberin, NEDD4, CD3, SPA1, B-Raf, p120GAP, inositol 1,4-bisphosphate, TCR alpha/beta, M-Ras, CalDAG-GEFIII, MAGI-1(BAIAP1), Adenylate cyclase type I, RAP-1A, CrkL, CALDAG-GEFI, ZAP70, G-protein alpha-s, KAP3, C3G, GGTase-I, cAMP, PLC-delta 1, ATP cytosol, Rap1GDS1, MR-GEF, 4.6.1.1, Ca('2+) cytosol, PKA-cat (cAMP-dependent), Rap1GAP1, DAG, RalGDS, c-Raf-1

Description

Rap1A signaling

RAP1A, member of RAS oncogene family ( RAP-1A) belongs to a family of small GTP-binding proteins (G-proteins) called monomeric G-proteins. The RAP subfamily consists of four members, RAP-1A, RAP-1B, RAP-2A and RAP-2B proteins [1], [2].

RAP-1A is a target of posttranslational modification via attachment of lipid moieties, such as geranyl, catalyzed by Geranylgeranyltransferase type I ( GGTase-I ). These posttranslational modifications affect localization and biological activity of RAP-1A [3], [4].

Like other G-proteins, RAP-1A is found in two interconvertible forms, GDP-bound inactive and GTP-bound active forms [5]. Conversion from GDP-bound form to GTP-bound is catalyzed by Guanine nucleotide exchange factors (GEFs). Rap GEF 1 ( C3G ), Calcium and DAG-regulated GEFs (e.g., RAS guanyl releasing protein 1 ( CALDAG-GEFI ) and RAS guanyl releasing protein 3 ( CalDAG-GEFIII )), Cyclic AMP ( cAMP )-dependent GEFs (e.g., Rap GEF 3 ( cAMP-GEFI ) and Rap GEF 4 ( cAMP-GEFII )), Rap GEF 5 ( MR-GEF ), and RAP1 GTP-GDP dissociation stimulator 1 ( Rap1GDS ) are known GEFs for RAP-1A. GEF first interacts with the GDP-bound form and releases bound GDP. As a result, a binary complex of the small G protein and GEF is formed. Then GEF in this complex is replaced by GTP resulting in formation of the GTP-bound small G protein.

GEF activity is regulated by an upstream signal. C3G is activated in response to T cell receptor ( TCR alpha/beta/ CD3 complex) stimulation via Zeta-chain (TCR) associated protein kinase 70kDa ( ZAP70 )/ v-Crk sarcoma virus CT10 oncogene homolog (avian)-like ( CrkL ) interaction. C3G interacts with the SH3 domain of CrkL and enhances GEF-activity of C3G [6].

Activity of CALDAG-GEFs and cAMP-GEFs is modulated by the second messengers. Binding of Calcium ( Ca(2+) ) and Diacylglycerol ( DAG ) to CALDAG-GEFs activate these GEFs. Cyclic AMP ( cAMP) activates cAMP-GEFs. Several signaling pathways, which regulate activity of Adenylate cyclase and Phospholipase C (e.g., PLC-delta ), are involved in modulating GEF-activity of CALDAG-GEFs and cAMP-GEFs [7], [8].

Phosphorylation of RAP-1A by cAMP-dependent protein kinase ( PKA ) leads to activation of RAP-1A [9].

Conversion from GTP-bound active form to GDP-bound inactive form is a result of intrinsic GTPase activity of RAP-1A. This activity is slow, and proteins called GTPase activated proteins (GAPs), e.g., Signal-induced proliferation-associated 1 ( SPA1 ), RAS p21 protein activator 3 ( RASA3 ), RAP1 GTPase activating protein ( Rap1GAP ), and Tuberous sclerosis 2 ( Tuberin ) , are known to stimulate it [10], [11], [12], [13].

GAP-activity is also regulated by several stimuli. Rap1GAP1 binds specifically to the alpha-subunits of the G(i) family (G-protein alpha-i family) of heterotrimeric G-proteins. Stimulation of the G(i)-coupled receptors translocates Rap1GAP1 from the cytosol to the membrane and decreases the amount of GTP-bound RAP-1A. This decrease in GTP-bound RAP-1A abolishes v-Raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 ) inactivation and activates Mitogen-activated protein kinase (ERK1/2) cascade [12].

RAP-1A binds to c-Raf-1 and competes with RAS proteins for binding to c-Raf-1, thereby antagonizing RAS-dependent activation of c-Raf-1 [14]. On the other hand, v-Raf murine sarcoma viral oncogene homolog B1 ( B-Raf ), another Raf family member, is activated by RAP-1A [15], [16].

Small G-proteins are also known to cross-talk with each other. RAP-1A modulates activity of RAL and RAS proteins via their respective effectors Ral guanine nucleotide dissociation stimulator ( RalGDS ) and RAS p21 protein activator 1 ( p120GAP ) [17], [18]. At the same time, another member of the RAS family, Muscle RAS oncogene homolog ( M-Ras ), regulates activity of RAP-1A exchange factor MR-GEF [19].

References:

  1. Hilgenfeld R
    Regulatory GTPases. Current opinion in structural biology 1995 Dec;5(6):810-7
  2. Cantrell DA
    GTPases and T cell activation. Immunological reviews 2003 Apr;192:122-30
  3. Buss JE, Quilliam LA, Kato K, Casey PJ, Solski PA, Wong G, Clark R, McCormick F, Bokoch GM, Der CJ
    The COOH-terminal domain of the Rap1A (Krev-1) protein is isoprenylated and supports transformation by an H-Ras:Rap1A chimeric protein. Molecular and cellular biology 1991 Mar;11(3):1523-30
  4. Danesi R, Figg WD, Reed E, Myers CE
    Paclitaxel (taxol) inhibits protein isoprenylation and induces apoptosis in PC-3 human prostate cancer cells. Molecular pharmacology 1995 Jun;47(6):1106-11
  5. Takai Y, Sasaki T, Matozaki T
    Small GTP-binding proteins. Physiological reviews 2001 Jan;81(1):153-208
  6. Gelkop S, Isakov N
    T cell activation stimulates the association of enzymatically active tyrosine-phosphorylated ZAP-70 with the Crk adapter proteins. The Journal of biological chemistry 1999 Jul 30;274(31):21519-27
  7. Clyde-Smith J, Silins G, Gartside M, Grimmond S, Etheridge M, Apolloni A, Hayward N, Hancock JF
    Characterization of RasGRP2, a plasma membrane-targeted, dual specificity Ras/Rap exchange factor. The Journal of biological chemistry 2000 Oct 13;275(41):32260-7
  8. de Rooij J, Rehmann H, van Triest M, Cool RH, Wittinghofer A, Bos JL
    Mechanism of regulation of the Epac family of cAMP-dependent RapGEFs. The Journal of biological chemistry 2000 Jul 7;275(27):20829-36
  9. Hata Y, Kaibuchi K, Kawamura S, Hiroyoshi M, Shirataki H, Takai Y
    Enhancement of the actions of smg p21 GDP/GTP exchange protein by the protein kinase A-catalyzed phosphorylation of smg p21. The Journal of biological chemistry 1991 Apr 5;266(10):6571-7
  10. Tsukamoto N, Hattori M, Yang H, Bos JL, Minato N
    Rap1 GTPase-activating protein SPA-1 negatively regulates cell adhesion. The Journal of biological chemistry 1999 Jun 25;274(26):18463-9
  11. Cullen PJ, Hsuan JJ, Truong O, Letcher AJ, Jackson TR, Dawson AP, Irvine RF
    Identification of a specific Ins(1,3,4,5)P4-binding protein as a member of the GAP1 family. Nature 1995 Aug 10;376(6540):527-30
  12. Mochizuki N, Ohba Y, Kiyokawa E, Kurata T, Murakami T, Ozaki T, Kitabatake A, Nagashima K, Matsuda M
    Activation of the ERK/MAPK pathway by an isoform of rap1GAP associated with G alpha(i) Nature 1999 Aug 26;400(6747):891-4
  13. Wienecke R, Maize JC Jr, Reed JA, de Gunzburg J, Yeung RS, DeClue JE
    Expression of the TSC2 product tuberin and its target Rap1 in normal human tissues. The American journal of pathology 1997 Jan;150(1):43-50
  14. Okada T, Hu CD, Jin TG, Kariya K, Yamawaki-Kataoka Y, Kataoka T
    The strength of interaction at the Raf cysteine-rich domain is a critical determinant of response of Raf to Ras family small GTPases. Molecular and cellular biology 1999 Sep;19(9):6057-64
  15. Grewal SS, Fass DM, Yao H, Ellig CL, Goodman RH, Stork PJ
    Calcium and cAMP signals differentially regulate cAMP-responsive element-binding protein function via a Rap1-extracellular signal-regulated kinase pathway. The Journal of biological chemistry 2000 Nov 3;275(44):34433-41
  16. Kolch W
    Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. The Biochemical journal 2000 Oct 15;351 Pt 2:289-305
  17. Spaargaren M, Bischoff JR
    Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap. Proceedings of the National Academy of Sciences of the United States of America 1994 Dec 20;91(26):12609-13
  18. Hata Y, Kikuchi A, Sasaki T, Schaber MD, Gibbs JB, Takai Y
    Inhibition of the ras p21 GTPase-activating protein-stimulated GTPase activity of c-Ha-ras p21 by smg p21 having the same putative effector domain as ras p21s. The Journal of biological chemistry 1990 May 5;265(13):7104-7
  19. Rebhun JF, Castro AF, Quilliam LA
    Identification of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interaction. The Journal of biological chemistry 2000 Nov 10;275(45):34901-8