G protein-coupled receptor kinase 6 (GRK6)
The protein contains 576 amino acids for an estimated molecular weight of 65991 Da.
Specifically phosphorylates the activated forms of G protein-coupled receptors. Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their desensitization. Seems to be involved in the desensitization of D2-like dopamine receptors in striatum and chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis (By similarity). Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor: LRP6 during Wnt signaling (in vitro). (updated: March 4, 2015)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
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.
This protein is annotated as membranous in Gene Ontology.
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The reference OMIM entry for this protein is 600869
G protein-coupled receptor kinase 6; grk6
Gprk6
CLONING
By PCR on neutrophil cDNA using primers based on sequences of known receptor kinases, Haribabu and Snyderman (1993) identified GPRK5 (600870) and GPRK6 sequences. Using a fragment of the GPRK6 PCR clone to screen a cDNA library, they isolated a cDNA encoding GPRK6. Sequence analysis predicted that the 544-amino acid GPRK6 protein contains the conserved DLG (asp-leu-gly) and ENIL (glu-asn-ile-leu) motifs. Northern blot analysis detected 2.1- and 2.9-kb GPRK6 transcripts in all tissues tested, with strongest expression in placenta and skeletal muscle. By screening a heart cDNA with the catalytic domains of BARK (ADRBK1; 109635), Benovic and Gomez (1993) isolated a cDNA encoding GRK6. The 576-amino acid GRK6 protein is 70% identical to GRK5. PAGE analysis showed expression of a 66-kD protein from an insect cell line.GENE FUNCTION
Benovic and Gomez (1993) found that GRK6 could phosphorylate rhodopsin (RHO; 180380) in a light-dependent manner and ADRB2 (109690) in an agonist-dependent manner. However, GRK6 was significantly less active than BARK or GRK5 on these substrates. Gaudreau et al. (2002) identified the leukotriene B4 receptor, BLT1 (LTB4R; 601531), as a substrate for GRK6. Thr308 in the BLT1 cytoplasmic tail was critical for inositol phosphate production and GRK6-mediated phosphorylation and desensitization of BLT1 signaling.MAPPING
By somatic cell hybrid analysis, Haribabu and Snyderman (1993) mapped the GPRK6 gene and a closely related gene to chromosomes 5 and 13, respectively. Bullrich et al. (1995) mapped GPRK6 to 5q35 by analysis of a rodent human hybrid panel. The GPRK6-related locus was found to map to 13pter-q21.ANIMAL MODEL
Gainetdinov et al. (2003) noted that some GRKs have been shown to phosphorylate G protein-coupled dopamine receptors, thereby regulating their activity and mediating desensitization of the receptors. Using immunohistochemistry, Gainetdinov et al. (2003) found that GRK6 is expressed in striatal neurons receiving dopaminergic input, and that postsynaptic D2/D3 dopamine receptors are physiologic targets of this kinase. GRK6 knockout mice showed supersensitivity to the locomotor-stimulating effects of psychostimulants, including cocaine and amphetamine. In addition, these mice demonstrated an enhanced coupling of striatal D2-like dopamine receptors to G proteins and augmented response to direct dopamine agonists. Gainetdinov et al. (2003) noted that supersensitivity of dopamine signaling has been postulated to be involved in several brain disorders, including addiction. Kavelaars et al. (2003) found that application of arachidonic acid to the ears of Grk6 -/- mice induced significantly increased inflammatory responses compared with wildtype mice. Neutrophils from Grk6 -/- mice responded to leukotriene B4 with a prolonged increase in intracellular calcium and actin polymerization. Kavelaars et al. (2003) concluded that GRK6 deficiency leads to prolonged BLT1 signaling and increased neutrophil migration. ... More on the omim web site
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 25, 2017: Additional information
No protein expression data in P. Mayeux work for GRK6
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 600869 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed