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GSKIP (GSK3-beta interaction protein)

Written2016-10Christine Bellanné-Chantelot, Isabelle Plo
Département de Génétique, Hpitaux Universitaires Pitié-Salpétrière-Charles Foix, Paris (CBC); INSERM UMR1170, Institut Gustave Roussy, Villejuif, (CBC, IP), France. christine.bellanne-chantelot@aphp.fr; isabelle.plo@gustaveroussy.fr

Abstract GSK3beta interaction protein (GSKIP) is a negative regulator of GSK3B (GSK3 beta) which is a highly conserved serine-threonine kinase involved in many cellular processes including glycogen metabolism, proliferation, differentiation, and development. GSKIP directly interacts with GSK3B through its C-terminal conserved GSK3B -binding domain (GID) and negatively regulates GSK3B in the Wnt/ beta -catenin signaling pathway. The overexpression of GSKIP may result in the activation of the Wnt pathway involved in hematopoietic stem cell homeostasis and normal megakaryopoiesis and in the development of leukemia stem cells in acute myeloid leukemia (AML). In a mouse model, GSK3B allelic deletion results in a myelodysplastic syndrome that, when combined with GSK3A deletion, leads to AML
The germline duplication of ATG2B and GSKIP, both located in 14q32.2, predisposes to the development of familial myeloproliferative neoplasms with autosomal dominant inheritance, in particular essential thrombocythemia progressing to leukemia. Overexpression of ATG2B and GSKIP enhances megakaryocyte progenitor differentiation by increasing progenitor sensitivity to thrombopoietin. Both genes cooperate with somatic JAK2, MPL and CALR mutations and their overexpression provides a growth advantage to hematopoietic cells carrying these driver mutations that may explain the familial aggregation and the progression of essential thrombocythemia to myelofibrosis and leukemia.

Keywords GSKIP; Myeloproliferative neoplasms (MPN); essential thrombocythemia; myelofibrosis; leukemia; predisposition; ATG2B/GSKIP; chromosome 14; CNV; autophagy; Wnt/beta-catenin pathway

(Note : for Links provided by Atlas : click)

Identity

Alias_namesC14orf129
chromosome 14 open reading frame 129
Other alias
HGNC (Hugo) GSKIP
LocusID (NCBI) 51527
Atlas_Id 64074
Location 14q32.2  [Link to chromosome band 14q32]
Location_base_pair Starts at 96831073 and ends at 96853627 bp from pter ( according to hg19-Feb_2009)  [Mapping GSKIP.png]
Local_order centromere to telomere.
Note cooperates with ATG2B, also located in 14q32.2 and included in the 700 kb duplication NC_000014.9:g.96.163.103_96.857.129dup (on Assembly GRCh37)

DNA/RNA

Description The GSKIP gene consists of 2 non-coding exons and 2 exons, spanning a coding region of 3433 bp.
Transcription There are four transcripts that differ by their 5'UTR and encode the same protein. The longest transcript (NM_001271904) of the GSKIP gene has a total total length of 1050 nucleotides.
Pseudogene Not yet identified.

Protein

Description The protein encoded by the GSKIP gene is the GSK3-beta interaction protein of 139 amino acids, with a calculated molecular mass of 15.648 kDa.
Expression Expression of GSKIP has been detected in various normal human tissues (bone marrow, whole blood, thymus, brain, heart, muscle, colon, kidney, liver, lung, pancreas, thyroid, salivary and adrenal glands, skin, ovary, uterus, placenta, prostate and testis). The gene is overexpressed in bone, colon and rectum.
In hematopoietic cells, GSKIP is expressed in CD34+ purified hematopoietic progenitors and CD36+ erythroblasts or CD41+ megakaryocytes derived from CD34+ progenitors cultured in vitro (Saliba et al, 2016)
Localisation GSKIP is localized in the cytoplasm and nucleus.
Function GSKIP belongs to the family of A-kinase anchoring proteins (AKAPs) that bind serine/threonine kinase (PKA). These AKAPs proteins interact with the regulatory domain of PKA and facilitate their phosphorylation. GSKIP directly interacts with GSK3B through its C-terminal conserved GSK3B-binding domain (GID; amino acid 115-139) and negatively regulates GSK3B in the Wnt/beta-catenin signaling pathway (Chou et al, 2006). The overexpression of GSKIP may mimic activation of the Wnt pathway involved in hematopoietic stem cell homeostasis and normal megakaryopoiesis (Li et al, 2008) and in the development of leukemia stem cells in AML (Wang. et al, 2010).

Mutations

Germinal A germline 14q32.2 head-to-tail duplication of 700 kb has been associated with familial myeloid malignancies (Saliba et al , 2015). The germline duplication includes the genes TCL1A, GSKIP, ATG2B, BDKRB1, BDKRB2 and the first exon of AK7. The overexpression of ATG2B and GSKIP that are expressed in myeloid cells, enhances hematopoietic progenitor differentiation, particularly of megacaryocytes. The development of myeloid malignancies required the cooperation of both genes with the myeloproliferative neoplasms (MPN) driver JAK2 Val617Phe mutation, MPL or CALR mutations. The mechanism of cooperation between ATG2B and GSKIP with MPN driver mutations remains unknown.
The germline duplication with the same distal and proximal breakpoints has only been identified in MPN families originated from West Indies (Martinique) suggesting a founder effect.

Implicated in

  
Entity Familial myeloproliferative neoplasms (MPN)
Disease Familial MPN originated from West-indies (Martinique) and in particular, essential thrombocythemia progressing to myelofibrosis and/or acute myeloid leukemia and primary myelofibrosis may be linked to ATG2B/GSKIP germline duplication. The predisposition is highly penetrant (80%) and is characterized by an earlier age of MPN onset in comparison to sporadic cases (41 years versus > 60 years). The spectrum of acquired driver mutations (JAK2 Val617Phe , MPL and CALR mutations) is similar to the spectrum of mutations in sporadic MPN cases.
Prognosis The percentage of transformation is close to 50% in these familial MPN cases and is related to the detection of mutations affecting epigenetic regulator genes such as TET2 IDH1 or IDH2.
  
  
Entity Acute myeloid leukemia (AML)
Disease AML originated from West-indies (Martinique) may be linked to ATG2B/GSKIP germline duplication.
Prognosis The prognosis of the disease is also linked to the detection of acquired mutations in TET2, IDH1 or in IDH2. No TP53 mutation was found, contrary to what was observed in AML evolving from MPN, suggesting a different pathway for leukemic transformation.
  

Bibliography

GSKIP is homologous to the Axin GSK3beta interaction domain and functions as a negative regulator of GSK3beta
Chou HY, Howng SL, Cheng TS, Hsiao YL, Lieu AS, Loh JK, Hwang SL, Lin CC, Hsu CM, Wang C, Lee CI, Lu PJ, Chou CK, Huang CY, Hong YR
Biochemistry. 2006;45:11379-89
PMID 16981698
 
Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is
Guezguez B, Almakadi M, Benoit YD, Shapovalova Z, Rahmig S, Fiebig-Comyn A, Casado FL, Tanasijevic B, Bresolin S, Masetti R, Doble BW, Bhatia M
Cancer Cell. 2016;29:61-74
PMID 26766591
 
GSK3beta is a negative regulator of platelet function and thrombosis.
Li D, August S, Woulfe DS
Blood 2008;111:3522-30
PMID 18218855
 
Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies
Saliba J, Saint-Martin C, Di Stefano A, Lenglet G, Marty C, Keren B, Pasquier F, Valle VD, Secardin L, Leroy G, Mahfoudhi E, Grosjean S, Droin N, Diop M, Dessen P, Charrier S, Palazzo A, Merlevede J, Meniane JC, Delaunay-Darivon C, Fuseau P, Isnard F, Casadevall N, Solary E, Debili N, Bernard OA, Raslova H, Najman A, Vainchenker W, Bellanné-Chantelot C, Plo I
Nat Genet. 2015;47:1131-40
PMID 26280900
 
The Wnt/beta-catenin pathway is required for the development of
Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, Zon LI,
Science. 2010;327(5973):1650-3
PMID 20339075
 

Citation

This paper should be referenced as such :
Bellanné-Chantelot C, Plo I
GSKIP (GSK3-beta interaction protein);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/GSKIPID64074ch14q32.html


Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ]
  Familial Myeloproliferative Disorders


External links

Nomenclature
HGNC (Hugo)GSKIP   20343
Cards
AtlasGSKIPID64074ch14q32
Entrez_Gene (NCBI)GSKIP  51527  GSK3B interacting protein
AliasesC14orf129; HSPC210
GeneCards (Weizmann)GSKIP
Ensembl hg19 (Hinxton)ENSG00000100744 [Gene_View]  chr14:96831073-96853627 [Contig_View]  GSKIP [Vega]
Ensembl hg38 (Hinxton)ENSG00000100744 [Gene_View]  chr14:96831073-96853627 [Contig_View]  GSKIP [Vega]
ICGC DataPortalENSG00000100744
TCGA cBioPortalGSKIP
AceView (NCBI)GSKIP
Genatlas (Paris)GSKIP
WikiGenes51527
SOURCE (Princeton)GSKIP
Genetics Home Reference (NIH)GSKIP
Genomic and cartography
GoldenPath hg19 (UCSC)GSKIP  -     chr14:96831073-96853627 +  14q32.2   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)GSKIP  -     14q32.2   [Description]    (hg38-Dec_2013)
EnsemblGSKIP - 14q32.2 [CytoView hg19]  GSKIP - 14q32.2 [CytoView hg38]
Mapping of homologs : NCBIGSKIP [Mapview hg19]  GSKIP [Mapview hg38]
Gene and transcription
Genbank (Entrez)AF151044 AK000796 AK094654 AK314423 BC004818
RefSeq transcript (Entrez)NM_001271904 NM_001271905 NM_001271906 NM_016472
RefSeq genomic (Entrez)NC_000014 NC_018925 NT_026437 NW_004929393
Consensus coding sequences : CCDS (NCBI)GSKIP
Cluster EST : UnigeneHs.745067 [ NCBI ]
CGAP (NCI)Hs.745067
Alternative Splicing GalleryENSG00000100744
Gene ExpressionGSKIP [ NCBI-GEO ]   GSKIP [ EBI - ARRAY_EXPRESS ]   GSKIP [ SEEK ]   GSKIP [ MEM ]
Gene Expression Viewer (FireBrowse)GSKIP [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)51527
GTEX Portal (Tissue expression)GSKIP
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9P0R6   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9P0R6  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9P0R6
Splice isoforms : SwissVarQ9P0R6
PhosPhoSitePlusQ9P0R6
Domains : Interpro (EBI)DUF727    GSKIP_dom   
Domain families : Pfam (Sanger)DUF727 (PF05303)   
Domain families : Pfam (NCBI)pfam05303   
Domain structure : Prodom (Prabi Lyon)DUF727 (PD080843)   
Conserved Domain (NCBI)GSKIP
DMDM Disease mutations51527
Blocks (Seattle)GSKIP
PDB (SRS)1SGO   
PDB (PDBSum)1SGO   
PDB (IMB)1SGO   
PDB (RSDB)1SGO   
Structural Biology KnowledgeBase1SGO   
SCOP (Structural Classification of Proteins)1SGO   
CATH (Classification of proteins structures)1SGO   
SuperfamilyQ9P0R6
Human Protein AtlasENSG00000100744
Peptide AtlasQ9P0R6
HPRD16601
IPIIPI00009374   IPI01026185   IPI01026069   
Protein Interaction databases
DIP (DOE-UCLA)Q9P0R6
IntAct (EBI)Q9P0R6
FunCoupENSG00000100744
BioGRIDGSKIP
STRING (EMBL)GSKIP
ZODIACGSKIP
Ontologies - Pathways
QuickGOQ9P0R6
Ontology : AmiGOcytoplasm  
Ontology : EGO-EBIcytoplasm  
NDEx NetworkGSKIP
Atlas of Cancer Signalling NetworkGSKIP
Wikipedia pathwaysGSKIP
Orthology - Evolution
OrthoDB51527
GeneTree (enSembl)ENSG00000100744
Phylogenetic Trees/Animal Genes : TreeFamGSKIP
HOVERGENQ9P0R6
HOGENOMQ9P0R6
Homologs : HomoloGeneGSKIP
Homology/Alignments : Family Browser (UCSC)GSKIP
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerGSKIP [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)GSKIP
dbVarGSKIP
ClinVarGSKIP
1000_GenomesGSKIP 
Exome Variant ServerGSKIP
ExAC (Exome Aggregation Consortium)GSKIP (select the gene name)
Genetic variants : HAPMAP51527
Genomic Variants (DGV)GSKIP [DGVbeta]
DECIPHER (Syndromes)14:96831073-96853627  ENSG00000100744
CONAN: Copy Number AnalysisGSKIP 
Mutations
ICGC Data PortalGSKIP 
TCGA Data PortalGSKIP 
Broad Tumor PortalGSKIP
OASIS PortalGSKIP [ Somatic mutations - Copy number]
Mutations and Diseases : HGMDGSKIP
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch GSKIP
DgiDB (Drug Gene Interaction Database)GSKIP
DoCM (Curated mutations)GSKIP (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)GSKIP (select a term)
intoGenGSKIP
Cancer3DGSKIP(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM
Orphanet
MedgenGSKIP
Genetic Testing Registry GSKIP
NextProtQ9P0R6 [Medical]
TSGene51527
GENETestsGSKIP
Huge Navigator GSKIP [HugePedia]
snp3D : Map Gene to Disease51527
BioCentury BCIQGSKIP
ClinGenGSKIP
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD51527
Chemical/Pharm GKB GenePA134987554
Clinical trialGSKIP
Miscellaneous
canSAR (ICR)GSKIP (select the gene name)
Probes
Litterature
PubMed16 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineGSKIP
EVEXGSKIP
GoPubMedGSKIP
iHOPGSKIP
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Apr 12 11:32:47 CEST 2017

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