RACK1 (receptor for activated C kinase 1)

2007-09-01   Mirna Mourtada-Maarabouni 

School of Life Sciences, Keele University, Keele, Staffs, ST5 5BG, United Kingdom

Identity

HGNC
LOCATION
5q35.3
LOCUSID
ALIAS
GNB2L1,Gnb2-rs1,H12.3,HLC-7,PIG21
FUSION GENES

DNA/RNA

Description

The gene spans approximatively 6.9 Kb. Orientation minus strand. Number of exons: 10.

Transcription

The length of GNB2L1 transcript is 951bp.

Proteins

Description

GNB2L1 encodes a cytosolic protein with a molecular mass of approximatively 35 kDa (317 amino acids). The protein has seven internal Trp-Asp 40 (WD40 domain) repeats. The WD40 repeats of RACK1/GNB2L1 are predicted to form a seven-bladed propeller structure, where each blade is composed of a four-stranded anti-parallel beta-sheet. The highly conserved WD repeat sequence of RACK1/GNB2L1 is found in a number of eukaryotic proteins and is implicated in a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly.

Expression

GNB2L1 is ubiquitously expressed in the tissues of higher mammals and humans including brain, liver, and spleen.

Localisation

GNB2L1 is a cytosolic protein.

Function

GNB2L1 was originally identified as an anchoring protein for protein kinase C beta (PKCbeta), which it stabilises in the active state and anchors to membranes or functional sites. However, evidence has accumulated to support a central role of RACK1/GNB2L1 in critical biological responses. In addition to binding specifically to the active form of PKCbeta isoforms, GNB2L1 also interacts with several other important signaling proteins including the Src kinase family, integrin beta1, integrin beta2, integrin beta3 and integrin beta5, beta-spectrin and dynamin, RasGAP, the androgen receptor , insulin-like growth factor 1 receptor (IGF-1r), Epstein-Barr virus trans-activator protein BZLF1, p73 and pRB.
This suggests that GNB2L1 may act as an anchor or adaptor protein, recruiting other proteins to various transmembrane receptors, providing a platform for protein-protein interactions and acting as the focus for several cell-signaling pathways. Accordingly, a number of cellular functions have been attributed to GNB2L1, e.g. in cell growth, adhesion, protrusion and chemotactic migration.
GNB2L1 might also have an effect on brain function; a reduction in GNB2L1 levels by around 50% has been reported in the brains of aged rats compared with adult or middle aged rat brains. GNB2L1 is also reported to be involved in number of functions in the nervous system. These include neurite growth, dendritic transport, glutamatergic and dopaminergic neurotransmissions and functioning of GABAA receptors.
In addition, up-regulation of GNB2L1 in lymphocytes results in suppression of apoptosis, indicating that it also plays an important role in the regulation of apoptosis. It is also reported that GNB2L1 inhibits the effects of adenovirus E1a on yeast, Saos osteosarcoma and HeLa cells, including the induction of apoptosis.
In addition, GNB2L1 over-expression was reported to protect PC-12 cell survival on withdrawal of Nerve Growth Factor.

Homology

GNB2L1 is homologous to the G protein beta subunit, having 42% identity with many conserved amino acid substitutions.

Mutations

Note

Mutations in the GNB2L1 gene have not been found in 274 samples from somatic cancer. However, GNB2L1 is reported to be up-regulated in angiogenesis and in human carcinomas.

Implicated in

Entity name
Brain pathologies and ageing
Disease
Changes in GNB2L1 levels were found in a number of brain pathologies and during ageing. GNB2L1 levels were significantly decreased in the cortex of patients with Down Syndrome, all of who develop Alzheimers disease as young adults. Association of GNB2L1 with PKC was put forward as a putative cause of the increase in PKC activity observed in the frontal cortex of subjects with bipolar disorder.
Entity name
Angiogenesis and tumor growth
Oncogenesis
GNB2L1 might contribute to angiogenesis and tumor growth, since it was shown to be up-regulated during angiogenesis in vitro and in vivo, and was also expressed in tumor angiogenesis. GNB2L1 expression was higher in human non-small cell lung and colon carcinomas than in the corresponding normal tissues.

Bibliography

Pubmed IDLast YearTitleAuthors
92929701997The role of anchoring protein RACK1 in PKC activation in the ageing rat brain.Battaini F et al
108490092000The PKC targeting protein RACK1 interacts with the Epstein-Barr virus activator protein BZLF1.Baumann M et al
110994742000RACK1 is up-regulated in angiogenesis and human carcinomas.Berns H et al
113091992001The WD protein Rack1 mediates protein kinase C and integrin-dependent cell migration.Buensuceso CS et al
124000052002RACK1: a novel substrate for the Src protein-tyrosine kinase.Chang BY et al
94420851998Rack1, a receptor for activated protein kinase C, interacts with integrin beta subunit.Liliental J et al
110409402000Frequent loss of heterozygosity on chromosome 5 in non-small cell lung carcinoma.Mendes-da-Silva P et al
94384081998Anchoring proteins for protein kinase C: a means for isozyme selectivity.Mochly-Rosen D et al
158702142005Functional expression cloning reveals a central role for the receptor for activated protein kinase C 1 (RACK1) in T cell apoptosis.Mourtada-Maarabouni M et al
167407122006Identification of specific gene copy number changes in asbestos-related lung cancer.Nymark P et al
127614932003Function of p73, not of p53, is inhibited by the physical interaction with RACK1 and its inhibitory effect is counteracted by pRB.Ozaki T et al
89314801996Functional impairment in protein kinase C by RACK1 (receptor for activated C kinase 1) deficiency in aged rat brain cortex.Pascale A et al
118246162002Aberrant expression of signaling-related proteins 14-3-3 gamma and RACK1 in fetal Down syndrome brain (trisomy 21).Peyrl A et al
129583112003The scaffolding protein RACK1 interacts with androgen receptor and promotes cross-talk through a protein kinase C signaling pathway.Rigas AC et al
83028541994Cloning of an intracellular receptor for protein kinase C: a homolog of the beta subunit of G proteins.Ron D et al
164579392006RACK1 has the nerve to act: structure meets function in the nervous system.Sklan EH et al
115437402001Increased association of brain protein kinase C with the receptor for activated C kinase-1 (RACK1) in bipolar affective disorder.Wang H et al
16441651992The WD-40 repeat.van der Voorn L et al

Other Information

Locus ID:

NCBI: 10399
MIM: 176981
HGNC: 4399
Ensembl: ENSG00000204628

Variants:

dbSNP: 10399
ClinVar: 10399
TCGA: ENSG00000204628
COSMIC: RACK1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000204628ENST00000376817J3KPE3
ENSG00000204628ENST00000502844D6R9Z1
ENSG00000204628ENST00000502905H0YAF8
ENSG00000204628ENST00000503081D6RBD0
ENSG00000204628ENST00000503494E9PD14
ENSG00000204628ENST00000504128H0YAM7
ENSG00000204628ENST00000504325D6R909
ENSG00000204628ENST00000504726D6RHJ5
ENSG00000204628ENST00000506312D6RGK8
ENSG00000204628ENST00000507000D6RFX4
ENSG00000204628ENST00000507756H0Y8W2
ENSG00000204628ENST00000508682D6RAU2
ENSG00000204628ENST00000509148H0Y9P0
ENSG00000204628ENST00000509535H0Y8R5
ENSG00000204628ENST00000510199D6R9L0
ENSG00000204628ENST00000511473D6RDI0
ENSG00000204628ENST00000511566D6RHH4
ENSG00000204628ENST00000511900D6RAC2
ENSG00000204628ENST00000512805P63244
ENSG00000204628ENST00000512805E9KL35
ENSG00000204628ENST00000512968D6REE5
ENSG00000204628ENST00000513027D6RFZ9
ENSG00000204628ENST00000514455D6RF23
ENSG00000204628ENST00000626067E9PD14

Expression (GTEx)

0
500
1000
1500

Pathways

PathwaySourceExternal ID
MeaslesKEGGko05162
MeaslesKEGGhsa05162
Signal TransductionREACTOMER-HSA-162582
Death Receptor SignallingREACTOMER-HSA-73887
TNF signalingREACTOMER-HSA-75893
TNFR1-induced NFkappaB signaling pathwayREACTOMER-HSA-5357956
TNFR1-mediated ceramide productionREACTOMER-HSA-5626978
Regulation of TNFR1 signalingREACTOMER-HSA-5357905

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
146548452003Release of eIF6 (p27BBP) from the 60S subunit allows 80S ribosome assembly.149
155779272004Regulation of eukaryotic translation by the RACK1 protein: a platform for signalling molecules on the ribosome.110
160611782005RACK1 mediates activation of JNK by protein kinase C [corrected].70
179650242007Calcineurin promotes hypoxia-inducible factor 1alpha expression by dephosphorylating RACK1 and blocking RACK1 dimerization.66
201037732010A crucial role for RACK1 in the regulation of glucose-stimulated IRE1alpha activation in pancreatic beta cells.63
281328432017ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Quality Control Function by Mediating Regulatory 40S Ribosomal Ubiquitylation.62
118846182002RACK1, an insulin-like growth factor I (IGF-I) receptor-interacting protein, modulates IGF-I-dependent integrin signaling and promotes cell spreading and contact with extracellular matrix.61
119348852002The anchoring protein RACK1 links protein kinase Cepsilon to integrin beta chains. Requirements for adhesion and motility.59
254169472014RACK1 controls IRES-mediated translation of viruses.53
166896832006Scanning peptide array analyses identify overlapping binding sites for the signalling scaffold proteins, beta-arrestin and RACK1, in cAMP-specific phosphodiesterase PDE4D5.52

Citation

Mirna Mourtada-Maarabouni

RACK1 (receptor for activated C kinase 1)

Atlas Genet Cytogenet Oncol Haematol. 2007-09-01

Online version: http://atlasgeneticsoncology.org/gene/43285/rack1