GSKIP (GSK3-beta interaction protein)

2016-10-01   Christine Bellanné-Chantelot , Isabelle Plo 

Identity

HGNC
LOCATION
14q32.2
LOCUSID
ALIAS
C14orf129

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

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 5UTR 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.

Proteins

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). It has recently been shown in a mouse model that Gsk3b allelic deletion results in a myelodysplastic syndrome that, when combined with GSK3A deletion, leads to AML (Guezguez et al, 2016).

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 name
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 name
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

Pubmed IDLast YearTitleAuthors
169816982006GSKIP is homologous to the Axin GSK3beta interaction domain and functions as a negative regulator of GSK3beta.Chou HY et al
267665912016GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is Predictive of Clinical Outcomes of Human Acute Leukemia.Guezguez B et al
182188552008GSK3beta is a negative regulator of platelet function and thrombosis.Li D et al
262809002015Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.Saliba J et al
203390752010The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML.Wang Y et al

Other Information

Locus ID:

NCBI: 51527
MIM: 616605
HGNC: 20343
Ensembl: ENSG00000100744

Variants:

dbSNP: 51527
ClinVar: 51527
TCGA: ENSG00000100744
COSMIC: GSKIP

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000100744ENST00000438650Q9P0R6
ENSG00000100744ENST00000438650A0A024R6P6
ENSG00000100744ENST00000553699G3V368
ENSG00000100744ENST00000554182Q9P0R6
ENSG00000100744ENST00000554182A0A024R6P6
ENSG00000100744ENST00000555181Q9P0R6
ENSG00000100744ENST00000555181A0A024R6P6
ENSG00000100744ENST00000555757G3V4I5
ENSG00000100744ENST00000556095Q9P0R6
ENSG00000100744ENST00000556095A0A024R6P6

Expression (GTEx)

0
5
10
15
20
25
30

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
262809002015Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.23
169816982006GSKIP is homologous to the Axin GSK3beta interaction domain and functions as a negative regulator of GSK3beta.18
274847982016The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3β Interaction Protein (GSKIP) Regulates β-Catenin through Its Interactions with Both Protein Kinase A (PKA) and GSK3β.8
213283102011Prediction of the binding mode between GSK3β and a peptide derived from GSKIP using molecular dynamics simulation.3
296949142018The origin of GSKIP, a multifaceted regulatory factor in the mammalian Wnt pathway.2

Citation

Christine Bellanné-Chantelot ; Isabelle Plo

GSKIP (GSK3-beta interaction protein)

Atlas Genet Cytogenet Oncol Haematol. 2016-10-01

Online version: http://atlasgeneticsoncology.org/gene/64074/gskip