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,, 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,, Ca('2+) cytosol, PKA-cat (cAMP-dependent), Rap1GAP1, DAG, RalGDS, c-Raf-1


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].


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    Paclitaxel (taxol) inhibits protein isoprenylation and induces apoptosis in PC-3 human prostate cancer cells. Molecular pharmacology 1995 Jun;47(6):1106-11
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    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
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    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
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    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