Induces morphological reversion of a cell line transformed by a Ras oncogene. Counteracts the mitogenic function of Ras, at least partly because it can interact with Ras GAPs and RAF in a competitive manner. Together with ITGB1BP1, regulates KRIT1 localization to microtubules and membranes. Plays a role in nerve growth factor (NGF)-induced neurite outgrowth. Plays a role in the regulation of embryonic blood vessel formation. Involved in the establishment of basal endothelial barrier function. May be involved in the regulation of the vascular endothelial growth factor receptor KDR expression at endothelial cell-cell junctions. (updated: April 1, 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: 100%

Model score: 0

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Biological Process

Activation of MAPKK activity

Adaptive immune response

Blood coagulation

Cellular response to cAMP

Cellular response to drug

Cellular response to glucose stimulus

Cellular response to nerve growth factor stimulus

Energy reserve metabolic process

Establishment of endothelial barrier

Liver regeneration

Negative regulation of collagen biosynthetic process

Negative regulation of synaptic vesicle exocytosis

Nerve growth factor signaling pathway

Nervous system development

Neurotrophin TRK receptor signaling pathway

Neutrophil degranulation

Platelet activation

Positive regulation of ERK1 and ERK2 cascade

Positive regulation of Fc-gamma receptor signaling pathway involved in phagocytosis

Positive regulation of glucose import

Positive regulation of GTPase activity

Positive regulation of neuron projection development

Positive regulation of protein kinase activity

Positive regulation of vasculogenesis

Protein localization to plasma membrane

Protein transport

Rap protein signal transduction

Regulation of cell junction assembly

Regulation of insulin secretion

Regulation of neurotransmitter receptor localization to postsynaptic specialization membrane

Response to antineoplastic agent

Response to carbohydrate

Signal transduction

Small molecule metabolic process

Cellular Component

Cell junction

Cytoplasm

Cytosol

Early endosome

Endosome membrane

Extracellular exosome

Glutamatergic synapse

Guanyl-nucleotide exchange factor complex

Late endosome

Myelin sheath

Neuron projection

Obsolete cell

Perinuclear region of cytoplasm

Phagocytic vesicle

Plasma membrane

Specific granule membrane

Molecular Function

G protein activity

GDP binding

GTP binding

GTPase activity

Guanyl-nucleotide exchange factor activity

Obsolete protein transporter activity

Protein complex binding

Protein-containing complex binding

Rap guanyl-nucleotide exchange factor activity

Small GTPase binding

The reference OMIM entry for this protein is 179520

Ras-related protein 1a; rap1a krev1

CLONING

Rousseau-Merck et al. (1990) stated that 3 human cDNAs encoding 'new' RAS-related proteins, designated RAP1A, RAP1B (179530), and RAP2 (179540), were isolated by Pizon et al. (1988) and Pizon et al. (1988). These proteins share approximately 50% amino acid identity with the classical RAS proteins and have numerous structural features in common. The most striking difference between the RAP and RAS proteins resides in their 61st amino acid: glutamine in RAS is replaced by threonine in RAP proteins. Kitayama et al. (1989) isolated a human cDNA termed Krev1 that can suppress the transformed phenotype of a Kirsten transformed cell line. The predicted amino acid sequence of the Krev1 protein is identical to that of RAP1A.

GENE FUNCTION

Boussiotis et al. (1997) noted that C3G (600303) catalyzes GTP exchange of Rap1. Immunoblot analysis showed that in anergic T cells, CBL (165360) is constitutively phosphorylated, CRKL (602007)-C3G complexes are recruited, and Rap1, an antagonist of Ras function and a negative regulator of IL2 transcription, is activated. Boussiotis et al. (1997) suggested that the key determinant of the functional outcome of T cell receptor-initiated signals may be the ratio of Ras-GTP to RAP1-GTP, with the predominance of the former enhancing, and the of the latter blocking, IL2 transcription. Asha et al. (1999) demonstrated that RAS1-mediated signaling pathways in Drosophila are not influenced by RAP1 levels, suggesting that RAS1 and RAP1 function via distinct pathways. Moreover, a mutation that abolishes the putative cAMP-dependent kinase phosphorylation site of Drosophila RAP1 can still rescue the RAP1 mutant phenotype. Asha et al. (1999) demonstrated that RAP1 is not needed for cell proliferation and cell-fate specification but has a critical function in regulating normal morphogenesis in the eye disc, the ovary, and the embryo. RAP1 mutations also disrupt cell migrations and cause abnormalities in cell shape. These findings indicate a role for RAP proteins as regulators of morphogenesis in vivo. Mochizuki et al. (2001) used fluorescent resonance energy transfer (FRET)-based sensors to evaluate the spatiotemporal images of growth factor-induced activation of RAS and RAP1. Epidermal growth factor (131530) activated RAS at the peripheral plasma membrane and RAP1 at the intracellular perinuclear region of COS-1 cells. In PC12 cells, nerve growth factor (see 162030)-induced activation of RAS was initiated at the plasma membrane and transmitted to the whole cell body. After 3 hours, high RAS activity was observed at the extending neurites. By using the FRAP (fluorescence recovery after photobleaching) technique, Mochizuki et al. (2001) found that RAS at the neurites turned over rapidly; therefore, the sustained RAS activity at neurites was due to high GTP/GDP exchange rate and/or low GTPase activity, but not to the retention of the active RAS. While previous biochemical analyses rarely detected more than 40% activation of RAS upon growth factor stimulation, Mochizuki et al. (2001) concluded that their data show that growth factor stimulation strongly activates RAS/RAP1 in a very restricted area within cells, and that a large population of RAS or RAP1 remains inactive, causing an apparent low-level response in biochemical assays. Zhu et al. (2002) examined the small GTPases RAS and RAP in the postsynaptic signaling underlying synaptic plasticity. They showed that RAS relays the NMDA receptor (see 1 ... 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 179520 was added.

Ras-related protein Rap-1A (RAP1A)