RAPGEF2

Members of the RAS (see HRAS; MIM 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 [PubMed 10934204]). [supplied by OMIM, Mar 2008]

Rap Guanine Nucleotide Exchange Factor 2

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 brain-derived neurotrophic factor (BDNF)-induced axon outgrowth of hippocampal neurons. Plays a role in the regulation of embryonic blood vessel formation and in the establishment of basal junction integrity and endothelial barrier function. May be involved in the regulation of the vascular endothelial growth factor receptor KDR and cadherin CDH5 expression at allantois endothelial cell-cell junctions.

Biological Process adenylate cyclase-activating adrenergic receptor signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process blood vessel developmentISS:UniProtKB
Biological Process brain-derived neurotrophic factor receptor signaling pathwayISS:UniProtKB
Biological Process cAMP-mediated signalingManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process cellular response to cAMPManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process cellular response to cGMPManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process cellular response to nerve growth factor stimulusISS:UniProtKB
Biological Process establishment of endothelial barrierManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process establishment of endothelial intestinal barrierManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process forebrain neuron developmentISS:UniProtKB
Biological Process G protein-coupled receptor signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process intracellular signal transductionManual Assertion Based On ExperimentTAS:UniProtKB
Biological Process MAPK cascade1 PublicationNAS:UniProtKB
Biological Process microvillus assemblyManual Assertion Based On ExperimentIGI:UniProtKB
Biological Process negative regulation of cell population proliferationManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process negative regulation of dendrite morphogenesisManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process negative regulation of melanin biosynthetic processISS:UniProtKB
Biological Process nerve growth factor signaling pathwayISS:UniProtKB
Biological Process neuron migrationISS:UniProtKB
Biological Process neuron projection developmentManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process neuropeptide signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of cAMP-dependent protein kinase activityManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of cAMP-mediated signalingManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of dendritic cell apoptotic processManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of ERK1 and ERK2 cascadeManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of GTPase activityManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of neuron migrationISS:UniProtKB
Biological Process positive regulation of neuron projection developmentISS:UniProtKB
Biological Process positive regulation of protein bindingISS:UniProtKB
Biological Process positive regulation of protein kinase activityManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of vasculogenesisISS:UniProtKB
Biological Process protein localization to plasma membraneManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process Rap protein signal transductionManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process Ras protein signal transductionManual Assertion Based On ExperimentIBA:GO_Central
Biological Process regulation of cell junction assemblyManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process regulation of synaptic plasticityISS:UniProtKB
Biological Process small GTPase mediated signal transductionManual Assertion Based On ExperimentTAS:UniProtKB
Biological Process ventricular system developmentISS:UniProtKB

Cytoplasm
Cytoplasm, perinuclear region
Cell membrane
Late endosome
Cell junction
Associated with the synaptic plasma membrane. Colocalizes with ADRB1 at the plasma membrane. Synaptosome. Enriched in synaptic plasma membrane and neuronal cell body. Colocalized with CTNNB1 at cell-cell contacts (By similarity).
Localized diffusely in the cytoplasm before neuronal growth factor (NGF) stimulation. Recruited to late endosomes after NGF stimulation. Colocalized with the high affinity nerve growth factor receptor NTRK1 at late endosomes. Translocated to the perinuclear region in a RAP1A-dependent manner. Translocated to the cell membrane.

Epilepsy, familial adult myoclonic, 7 (FAME7):
A form of familial myoclonic epilepsy, a neurologic disorder characterized by cortical hand tremors, myoclonic jerks and occasional generalized or focal seizures with a non-progressive or very slowly progressive disease course. Usually, myoclonic tremor is the presenting symptom, characterized by tremulous finger movements and myoclonic jerks of the limbs increased by action and posture. In a minority of patients, seizures are the presenting symptom. Some patients exhibit mild cognitive impairment. FAME7 inheritance is autosomal dominant.

Ubiquitinated by NEDD4, leading to proteasomal degradation.
Phosphorylation by PLK2 promotes its activity.