Functions as a guanine nucleotide exchange factor (GEF), which activates Rap and Ras family of small GTPases by exchanging bound GDP for free GTP in a cAMP-dependent manner. Serves as a link between cell surface receptors and Rap/Ras GTPases in intracellular signaling cascades. Acts also as an effector for Rap1 by direct association with Rap1-GTP thereby leading to the amplification of Rap1-mediated signaling. Shows weak activity on HRAS. It is controversial whether RAPGEF2 binds cAMP and cGMP (PubMed:23800469, PubMed:10801446) or not (PubMed:10608844, PubMed:10548487, PubMed:11359771). Its binding to ligand-activated beta-1 adrenergic receptor ADRB1 leads to the Ras activation through the G(s)-alpha signaling pathway. Involved in the cAMP-induced Ras and Erk1/2 signaling pathway that leads to sustained inhibition of long term melanogenesis by reducing dendrite extension and melanin synthesis. Provides also inhibitory signals for cell proliferation of melanoma cells and promotes their apoptosis in a cAMP-independent nanner. Regulates cAMP-induced neuritogenesis by mediating the Rap1/B-Raf/ERK signaling through a pathway that is independent on both PKA and RAPGEF3/RAPGEF4. Involved in neuron migration and in the formation of the major forebrain fiber connections forming the corpus callosum, the anterior commissure and the hippocampal commissure during brain development. Involved in neuronal growth factor (NGF)-induced sustained activation of Rap1 at late endosomes and in brai (updated: March 4, 2015)

Protein identification was indicated in the following studies:

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

Publication	Identification ¹	Uniprot mapping ²	Not mapped / Obsolete	TrEMBL	Swiss-Prot
Goodman (2013)	2289 (gene list)	2278	53	20599	2269
Lange (2014)	1234	1234	7	28	1224
Hegedus (2015)	2638	2622	0	235	2387
Wilson (2016)	1658	1528	170	291	1068
d'Alessandro (2017)	1826	1817	2	0	1815
Bryk (2017)	2090	2060	10	108	1942
Chu (2018)	1853	1804	55	362	1387

¹ as available in the article and/or in supplementary material
² uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

Protein sequence (FASTA)

Protein coevolution profile (FreeContact)

Multiple Sequence Alignment (Muscle)

This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.

Total structural coverage: 9%

Model score: 0

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Biological Process

Adenylate cyclase-activating adrenergic receptor signaling pathway

Blood vessel development

Brain-derived neurotrophic factor receptor signaling pathway

CAMP-mediated signaling

Cellular response to cAMP

Cellular response to cGMP

Cellular response to nerve growth factor stimulus

Establishment of endothelial barrier

Establishment of endothelial intestinal barrier

Forebrain neuron development

G protein-coupled receptor signaling pathway

Intracellular signal transduction

MAPK cascade

Microvillus assembly

Negative regulation of cell population proliferation

Negative regulation of dendrite morphogenesis

Negative regulation of melanin biosynthetic process

Nerve growth factor signaling pathway

Neuron migration

Neuron projection development

Neuropeptide signaling pathway

Positive regulation of cAMP-dependent protein kinase activity

Positive regulation of cAMP-mediated signaling

Positive regulation of dendritic cell apoptotic process

Positive regulation of ERK1 and ERK2 cascade

Positive regulation of GTPase activity

Positive regulation of neuron migration

Positive regulation of neuron projection development

Positive regulation of protein binding

Positive regulation of protein kinase activity

Positive regulation of vasculogenesis

Protein localization to plasma membrane

Rap protein signal transduction

Regulation of cell junction assembly

Regulation of synaptic plasticity

Small GTPase mediated signal transduction

Ventricular system development

Cellular Component

Apical plasma membrane

Bicellular tight junction

Cell-cell junction

Cytoplasm

Cytosol

Endocytic vesicle

Integral component of plasma membrane

Late endosome

Membrane

Neuron projection

Neuronal cell body

Perinuclear region of cytoplasm

Plasma membrane

Protein complex

Protein-containing complex

Synapse

Molecular Function

Beta-1 adrenergic receptor binding

Calcium ion binding

CAMP binding

Diacylglycerol binding

GTPase activator activity

Guanyl-nucleotide exchange factor activity

Obsolete signal transducer activity

PDZ domain binding

Phosphatidic acid binding

Rap guanyl-nucleotide exchange factor activity

Ras guanyl-nucleotide exchange factor activity

WW domain binding

The reference OMIM entry for this protein is 609530

Rap guanine nucleotide exchange factor 2; rapgef2
Neural rap guanine nucleotide exchange protein; nrapgep
Ras-associating guanine nucleotide exchange factor; ragef
Pdz domain-containing guanine nucleotide exchange factor 1; pdzgef1
Kiaa0313

DESCRIPTION

Members of the RAS (see HRAS; 190020) subfamily of GTPases function in signal transduction as GTP/GDP-regulated switches that cycle between inactive GDP- and active GTP-bound states. Guanine nucleotide exchange factors (GEFs), such as RAPGEF2, serve as RAS activators by promoting acquisition of GTP to maintain the active GTP-bound state and are the key link between cell surface receptors and RAS activation (Rebhun et al., 2000).

CLONING

By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1997) cloned RAPGEF2, which they designated KIAA0313. The deduced 1,499-amino acid protein has an apparent molecular mass of more than 100 kD, and it shares significant amino acid identity with RAPGEF5 (609527). RT-PCR detected high RAPGEF2 expression in kidney, placenta, and liver, intermediate expression in ovary, and low expression in small intestine, brain, and lung. No expression was detected in other tissues examined. Ohtsuka et al. (1999) determined that RAPGEF2, which they called NRAPGEP, contains an incomplete cAMP-binding region (RCBD), followed by a PDZ domain, a RAS association domain, a RAS GDP/GTP exchange protein domain, and a C-terminal consensus PDZ-binding motif. Using Northern blot analysis, de Rooij et al. (1999) detected expression of RAPGEF2, which they called PDZGEF1, in all tissues examined. Western blot analysis detected PDZGEF1 protein at an apparent molecular mass of 200 kD in cell lines derived from several tissues and various species. De Rooij et al. (1999) identified a RAS exchange motif (REM) between the RCBD and PDZ domain in the N-terminal half of PDZGEF1.

GENE FUNCTION

Ohtsuka et al. (1999) found that recombinant RAPGEF2 stimulated dissociation of GDP from RAP1B (179530) and binding of a nonhydrolyzable GTP analog to RAP1B in dose- and time-dependent manners. RAPGEF2 did not show GEP activity for other small G proteins tested, and its activity was not affected by cAMP. Ohtsuka et al. (1999) found that mouse Rapgef2 interacted with a synaptic scaffold protein, Sscam (MAGI2; 606382), and by blot overlay and coimmunoprecipitation assays, they found that human RAPGEF2 also interacted with mouse Sscam. Mutation analysis indicated that the second PDZ domain of Sscam bound to the C-terminal PDZ-binding motif of RAPGEF2. Since rat Rapgef2 showed abundant expression in brain, and the protein was enriched in synaptic plasma membrane vesicles, Ohtsuka et al. (1999) hypothesized that RAPGEF2 may play a role at the synapse. De Rooij et al. (1999) showed that PDZGEF1 increased binding of GTP to RAP1A (179520) and RAP1B following transfection in COS-7 cells, but it did not increase the amount of GTP bound to other small G proteins. cAMP and cGMP had no effect on the GEF activity of PDZGEF1. By assaying the GEF activity of truncated proteins, de Rooij et al. (1999) determined that RCBD is a GEF inhibitory domain. Liao et al. (1999) found that RAGEF bound RAP1A in a GTP-dependent manner through its RAS association domain, and it stimulated GDP/GTP exchange of RAP1A in vitro and in vivo through its REM and GEF domains. RAGEF failed to bind cAMP or cGMP. Rebhun et al. (2000) showed that PDZGEF specifically bound RAP1A- and RAP2B (179541)-GTP. They found that PDZGEF induced ELK1 (311040)-mediated reporter gene expression. Kawajiri et al. (2000) found that human RAPGEF2 interacted with mouse beta-catenin (CTNNB1; 116806). Coimmunoprecipitation assays indicate ... More on the omim web site

Subscribe to this protein entry history

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 609530 was added.

Rap guanine nucleotide exchange factor 2 (RAPGEF2)