RAPGEF2 Rap guanine nucleotide exchange factor 2 [Homo sapiens (human)] - Gene

Summary

Official Symbol: RAPGEF2provided by HGNC
Official Full Name: Rap guanine nucleotide exchange factor 2provided by HGNC
Primary source: HGNC:HGNC:16854
See related: Ensembl:ENSG00000109756 MIM:609530; AllianceGenome:HGNC:16854
Gene type: protein coding
RefSeq status: VALIDATED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: RAGEF; RA-GEF; NRAPGEP; PDZGEF1; Rap-GEP; CNrasGEF; PDZ-GEF1; RA-GEF-1; nRap GEP
Summary: 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]
Expression: Ubiquitous expression in brain (RPKM 13.6), bone marrow (RPKM 11.0) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 4q32.1

Exon count:: 34

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	4	NC_000004.12 (159103079..159360173)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	4	NC_060928.1 (162453893..162710940)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	4	NC_000004.11 (160024231..160281325)

Chromosome 4 - NC_000004.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: Tissue-specific circular RNA induction during human fetal development
Description: 35 human fetal samples from 6 tissues (3 - 7 replicates per tissue) collected between 10 and 20 weeks gestational time were sequenced using Illumina TruSeq Stranded Total RNA
BioProject: PRJNA270632
Publication: PMID 26076956
Analysis date: Mon Apr 2 22:54:59 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

RAPGEF2 mediates oligomeric Abeta-induced synaptic loss and cognitive dysfunction in the 3xTg-AD mouse model of Alzheimer's disease.
Title: RAPGEF2 mediates oligomeric Aβ-induced synaptic loss and cognitive dysfunction in the 3xTg-AD mouse model of Alzheimer's disease.
Disruption of MAGI2-RapGEF2-Rap1 signaling contributes to podocyte dysfunction in congenital nephrotic syndrome caused by mutations in MAGI2.
Title: Disruption of MAGI2-RapGEF2-Rap1 signaling contributes to podocyte dysfunction in congenital nephrotic syndrome caused by mutations in MAGI2.
Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex.
Title: Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex.
local accumulation of PDZGEF at the apical membrane during establishment of epithelial polarity is mediated by electrostatic interactions between positively charged side chains in the PDZ domain and negatively charged phosphatidic acid.
Title: The PDZ domain of the guanine nucleotide exchange factor PDZGEF directs binding to phosphatidic acid during brush border formation.
SCF(FBXW11) bound, polyubiquitylated, and destabilized RAPGEF2, a guanine nucleotide exchange factor that activates the small GTPase RAP1
Title: Substrate trapping proteomics reveals targets of the βTrCP2/FBXW11 ubiquitin ligase.
JAM-A regulates epithelial permeability via association with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and control contraction of the apical cytoskeleton.
Title: JAM-A associates with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and regulate epithelial barrier function.
NEDD4-1 regulates cell migration and invasion through ubiquitination of CNrasGEF in vitro.
Title: NEDD4-1 regulates migration and invasion of glioma cells through CNrasGEF ubiquitination in vitro.
We report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-beta and casein kinase-1alpha and consequently degraded by the proteasome.
Title: Control of epithelial cell migration and invasion by the IKKβ- and CK1α-mediated degradation of RAPGEF2.
Data indicate that expression of Rapgef2 in embryonic kidney 293T cells enables cAMP-Rap1-ERK signaling.
Title: Rapgef2 connects GPCR-mediated cAMP signals to ERK activation in neuronal and endocrine cells.
DNA methylation shows genome-wide association of NFIX, RAPGEF2 and MSRB3 with gestational age at birth.
Title: DNA methylation shows genome-wide association of NFIX, RAPGEF2 and MSRB3 with gestational age at birth.

Submit: New GeneRIF Correction See all GeneRIFs (14)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Epilepsy, familial adult myoclonic, 7 MedGen: C4748080 OMIM: 618075 GeneReviews: Not available	Compare labs

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

STS-H47114 (e-PCR)
- UniSTS:56089

RH45436 (e-PCR)
- UniSTS:63542

WI-20985 (e-PCR)
- UniSTS:69193

STS-T86195 (e-PCR)
- UniSTS:59008

SHGC-59760 (e-PCR)
- UniSTS:62084

A006Q46 (e-PCR)
- UniSTS:60065

SHGC-110526 (e-PCR)
- UniSTS:167884

RH93702 (e-PCR)
- UniSTS:92401

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables GTPase activator activity	IDA Inferred from Direct Assay more info	PubMed
enables PDZ domain binding	IDA Inferred from Direct Assay more info	PubMed
enables WW domain binding	IDA Inferred from Direct Assay more info	PubMed
enables beta-1 adrenergic receptor binding	IDA Inferred from Direct Assay more info	PubMed
NOT enables cAMP binding	IDA Inferred from Direct Assay more info	PubMed
enables cAMP binding	IDA Inferred from Direct Assay more info	PubMed
NOT enables cGMP binding	IDA Inferred from Direct Assay more info	PubMed
enables calcium ion binding	NAS Non-traceable Author Statement more info	PubMed
enables diacylglycerol binding	NAS Non-traceable Author Statement more info	PubMed
enables guanyl-nucleotide exchange factor activity	IBA Inferred from Biological aspect of Ancestor more info
enables guanyl-nucleotide exchange factor activity	IDA Inferred from Direct Assay more info	PubMed
enables phosphatidic acid binding	IDA Inferred from Direct Assay more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed

Process	Evidence Code	Pubs
involved_in G protein-coupled receptor signaling pathway	IDA Inferred from Direct Assay more info	PubMed
involved_in MAPK cascade	NAS Non-traceable Author Statement more info	PubMed
involved_in Rap protein signal transduction	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in Ras protein signal transduction	IBA Inferred from Biological aspect of Ancestor more info
involved_in adenylate cyclase-activating adrenergic receptor signaling pathway	IDA Inferred from Direct Assay more info	PubMed
involved_in adenylate cyclase-modulating G protein-coupled receptor signaling pathway	IDA Inferred from Direct Assay more info	PubMed
involved_in blood vessel development	ISS Inferred from Sequence or Structural Similarity more info
involved_in brain-derived neurotrophic factor receptor signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
involved_in cAMP-mediated signaling	NAS Non-traceable Author Statement more info	PubMed
involved_in cellular response to cAMP	IDA Inferred from Direct Assay more info	PubMed
involved_in cellular response to cGMP	IDA Inferred from Direct Assay more info	PubMed
involved_in cellular response to nerve growth factor stimulus	ISS Inferred from Sequence or Structural Similarity more info
involved_in establishment of endothelial barrier	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in establishment of endothelial intestinal barrier	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in forebrain neuron development	ISS Inferred from Sequence or Structural Similarity more info
involved_in intracellular signal transduction	TAS Traceable Author Statement more info	PubMed
involved_in microvillus assembly	IGI Inferred from Genetic Interaction more info	PubMed
involved_in negative regulation of cell population proliferation	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of dendrite morphogenesis	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of melanin biosynthetic process	ISS Inferred from Sequence or Structural Similarity more info
involved_in nerve growth factor signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
involved_in neuron migration	ISS Inferred from Sequence or Structural Similarity more info
involved_in neuron projection development	IDA Inferred from Direct Assay more info	PubMed
involved_in neuropeptide signaling pathway	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of ERK1 and ERK2 cascade	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of GTPase activity	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of GTPase activity	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of cAMP-dependent protein kinase activity	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of dendritic cell apoptotic process	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of neuron migration	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of neuron projection development	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of protein binding	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of protein kinase activity	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of vasculogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in protein localization to plasma membrane	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of cell junction assembly	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of synaptic plasticity	ISS Inferred from Sequence or Structural Similarity more info
involved_in small GTPase-mediated signal transduction	TAS Traceable Author Statement more info	PubMed
involved_in ventricular system development	ISS Inferred from Sequence or Structural Similarity more info

Component	Evidence Code	Pubs
is_active_in apical plasma membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in apical plasma membrane	IDA Inferred from Direct Assay more info	PubMed
located_in bicellular tight junction	IDA Inferred from Direct Assay more info	PubMed
located_in cell-cell junction	ISS Inferred from Sequence or Structural Similarity more info
located_in cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	TAS Traceable Author Statement more info
is_active_in endocytic vesicle	IBA Inferred from Biological aspect of Ancestor more info
located_in endocytic vesicle	IDA Inferred from Direct Assay more info	PubMed
located_in late endosome	IDA Inferred from Direct Assay more info	PubMed
located_in membrane	IDA Inferred from Direct Assay more info	PubMed
located_in neuron projection	ISS Inferred from Sequence or Structural Similarity more info
located_in neuronal cell body	ISS Inferred from Sequence or Structural Similarity more info
located_in perinuclear region of cytoplasm	IDA Inferred from Direct Assay more info	PubMed
is_active_in plasma membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in plasma membrane	IDA Inferred from Direct Assay more info
located_in plasma membrane	ISS Inferred from Sequence or Structural Similarity more info
located_in plasma membrane	NAS Non-traceable Author Statement more info	PubMed
part_of protein-containing complex	ISS Inferred from Sequence or Structural Similarity more info
located_in synapse	ISS Inferred from Sequence or Structural Similarity more info

General protein information

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Preferred Names: rap guanine nucleotide exchange factor 2

Names: PDZ domain containing guanine nucleotide exchange factor (GEF) 1; PDZ domain-containing guanine nucleotide exchange factor 1; RA(Ras/Rap1A-associating)-GEF; Rap guanine nucleotide exchange factor (GEF) 2; cyclic nucleotide ras GEF; neural RAP guanine nucleotide exchange protein; ras/Rap1-associating GEF-1

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_063926.1 RefSeqGene

Range

4011..261105

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001351724.5 → NP_001338653.1 rap guanine nucleotide exchange factor 2 isoform 1

Status: VALIDATED

Source sequence(s)

AC074344, AC095064, AC105316

UniProtKB/TrEMBL

A0A2R8Y661

Related

ENSP00000495906.1, ENST00000644474.1

Conserved Domains (7) summary

smart00100
Location:297 → 412

cNMP; Cyclic nucleotide-monophosphate binding domain

smart00229
Location:428 → 541

RasGEFN; Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif

cd00038
Location:37 → 143

CAP_ED; effector domain of the CAP family of transcription factors; members include CAP (or cAMP receptor protein (CRP)), which binds cAMP, FNR (fumarate and nitrate reduction), which uses an iron-sulfur cluster to sense oxygen) and CooA, a heme containing CO ...

cd00155
Location:874 → 1099

RasGEF; Guanine nucleotide exchange factor for Ras-like small GTPases. Small GTP-binding proteins of the Ras superfamily function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. ...

cd00992
Location:545 → 625

PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...

TIGR02037
Location:565 → 689

degP_htrA_DO; periplasmic serine protease, Do/DeqQ family

cd01785
Location:769 → 851

RA_PDZ-GEF1; Ras-associating (RA) domain found in PDZ domain-containing guanine nucleotide exchange factor 1 (PDZ-GEF1) and similar proteins
NM_001351725.2 → NP_001338654.1 rap guanine nucleotide exchange factor 2 isoform 2

Status: VALIDATED

Source sequence(s)

AC074344, AC105316

UniProtKB/TrEMBL

A0A2R8Y661

Conserved Domains (6) summary

smart00100
Location:181 → 296

cNMP; Cyclic nucleotide-monophosphate binding domain

smart00229
Location:312 → 425

RasGEFN; Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif

cd00155
Location:758 → 983

RasGEF; Guanine nucleotide exchange factor for Ras-like small GTPases. Small GTP-binding proteins of the Ras superfamily function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. ...

cd00992
Location:429 → 509

PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...

cl00155
Location:651 → 735

UBQ; Ubiquitin-like proteins

cl28339
Location:449 → 573

DegQ; Periplasmic serine protease, S1-C subfamily, contain C-terminal PDZ domain [Posttranslational modification, protein turnover, chaperones]
NM_001351726.3 → NP_001338655.1 rap guanine nucleotide exchange factor 2 isoform 2

Status: VALIDATED

Source sequence(s)

AC074344, AC105316

UniProtKB/TrEMBL

A0A2R8Y661

Conserved Domains (6) summary

smart00100
Location:181 → 296

cNMP; Cyclic nucleotide-monophosphate binding domain

smart00229
Location:312 → 425

RasGEFN; Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif

cd00155
Location:758 → 983

RasGEF; Guanine nucleotide exchange factor for Ras-like small GTPases. Small GTP-binding proteins of the Ras superfamily function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. ...

cd00992
Location:429 → 509

PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...

cl00155
Location:651 → 735

UBQ; Ubiquitin-like proteins

cl28339
Location:449 → 573

DegQ; Periplasmic serine protease, S1-C subfamily, contain C-terminal PDZ domain [Posttranslational modification, protein turnover, chaperones]
NM_001351727.4 → NP_001338656.1 rap guanine nucleotide exchange factor 2 isoform 3

Status: VALIDATED

Source sequence(s)

AC074344, AC105316

UniProtKB/TrEMBL

Q17RH5

Related

ENSP00000495298.1, ENST00000644902.1

Conserved Domains (6) summary

smart00100
Location:136 → 251

cNMP; Cyclic nucleotide-monophosphate binding domain

smart00229
Location:267 → 380

RasGEFN; Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif

cd00155
Location:713 → 938

RasGEF; Guanine nucleotide exchange factor for Ras-like small GTPases. Small GTP-binding proteins of the Ras superfamily function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. ...

cd00992
Location:384 → 464

PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...

TIGR02037
Location:404 → 528

degP_htrA_DO; periplasmic serine protease, Do/DeqQ family

cd01785
Location:608 → 690

RA_PDZ-GEF1; Ras-associating (RA) domain found in PDZ domain-containing guanine nucleotide exchange factor 1 (PDZ-GEF1) and similar proteins
NM_001351728.4 → NP_001338657.1 rap guanine nucleotide exchange factor 2 isoform 4

Status: VALIDATED

Source sequence(s)

AC074344, AC105316

Consensus CDS

CCDS93663.1

UniProtKB/TrEMBL

A0A994J7S7, Q17RH5

Related

ENSP00000516108.1, ENST00000505026.2

Conserved Domains (6) summary

smart00100
Location:136 → 251

cNMP; Cyclic nucleotide-monophosphate binding domain

smart00229
Location:267 → 380

RasGEFN; Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif

cd00155
Location:713 → 938

RasGEF; Guanine nucleotide exchange factor for Ras-like small GTPases. Small GTP-binding proteins of the Ras superfamily function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. ...

cd00992
Location:384 → 464

PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...

TIGR02037
Location:404 → 528

degP_htrA_DO; periplasmic serine protease, Do/DeqQ family

cd01785
Location:608 → 690

RA_PDZ-GEF1; Ras-associating (RA) domain found in PDZ domain-containing guanine nucleotide exchange factor 1 (PDZ-GEF1) and similar proteins
NM_001394067.2 → NP_001380996.1 rap guanine nucleotide exchange factor 2 isoform 6

Status: VALIDATED

Source sequence(s)

AC074344, AC095064, AC105316

Consensus CDS

CCDS93662.1

UniProtKB/TrEMBL

A0A2R8Y661, A0A8I5KZ40

Related

ENSP00000510694.1, ENST00000691494.1

Conserved Domains (6) summary

smart00100
Location:297 → 412

cNMP; Cyclic nucleotide-monophosphate binding domain

smart00229
Location:428 → 541

RasGEFN; Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif

cd00038
Location:37 → 143

CAP_ED; effector domain of the CAP family of transcription factors; members include CAP (or cAMP receptor protein (CRP)), which binds cAMP, FNR (fumarate and nitrate reduction), which uses an iron-sulfur cluster to sense oxygen) and CooA, a heme containing CO ...

cd00155
Location:874 → 1099

RasGEF; Guanine nucleotide exchange factor for Ras-like small GTPases. Small GTP-binding proteins of the Ras superfamily function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. ...

cd00992
Location:545 → 625

PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...

cd01785
Location:769 → 851

RA_PDZ-GEF1; Ras-associating (RA) domain found in PDZ domain-containing guanine nucleotide exchange factor 1 (PDZ-GEF1) and similar proteins
NM_014247.5 → NP_055062.1 rap guanine nucleotide exchange factor 2 isoform 5

See identical proteins and their annotated locations for NP_055062.1

Status: VALIDATED

Source sequence(s)

AC074344, AC105316

Consensus CDS

CCDS43277.1

UniProtKB/Swiss-Prot

D3DP27, Q9Y4G8

UniProtKB/TrEMBL

Q17RH5

Related

ENSP00000264431.4, ENST00000264431.8

Conserved Domains (6) summary

smart00100
Location:136 → 251

cNMP; Cyclic nucleotide-monophosphate binding domain

smart00229
Location:267 → 380

RasGEFN; Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif

cd00155
Location:713 → 938

RasGEF; Guanine nucleotide exchange factor for Ras-like small GTPases. Small GTP-binding proteins of the Ras superfamily function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. ...

cd00992
Location:384 → 464

PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...

TIGR02037
Location:404 → 528

degP_htrA_DO; periplasmic serine protease, Do/DeqQ family

cd01785
Location:608 → 690

RA_PDZ-GEF1; Ras-associating (RA) domain found in PDZ domain-containing guanine nucleotide exchange factor 1 (PDZ-GEF1) and similar proteins