GSKIP (GSK3-beta interaction protein)
2016-10-01 Christine Bellanné-Chantelot , Isabelle Plo AffiliationAbstract
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)
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.
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
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
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.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 16981698 | 2006 | GSKIP is homologous to the Axin GSK3beta interaction domain and functions as a negative regulator of GSK3beta. | Chou HY et al |
| 26766591 | 2016 | GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is Predictive of Clinical Outcomes of Human Acute Leukemia. | Guezguez B et al |
| 18218855 | 2008 | GSK3beta is a negative regulator of platelet function and thrombosis. | Li D et al |
| 26280900 | 2015 | Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies. | Saliba J et al |
| 20339075 | 2010 | The 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
Expression (GTEx)
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 34172895 | 2022 | Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms. | 8 |
| 34748402 | 2022 | Loss of Atg2b and Gskip Impairs the Maintenance of the Hematopoietic Stem Cell Pool Size. | 2 |
| 36550871 | 2022 | High expression of GSKIP is associated with poor prognosis in meningioma. | 0 |
| 34172895 | 2022 | Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms. | 8 |
| 34748402 | 2022 | Loss of Atg2b and Gskip Impairs the Maintenance of the Hematopoietic Stem Cell Pool Size. | 2 |
| 36550871 | 2022 | High expression of GSKIP is associated with poor prognosis in meningioma. | 0 |
| 33554699 | 2021 | ATG2B/GSKIP in de novo acute myeloid leukemia (AML): high prevalence of germline predisposition in French West Indies. | 2 |
| 33554699 | 2021 | ATG2B/GSKIP in de novo acute myeloid leukemia (AML): high prevalence of germline predisposition in French West Indies. | 2 |
| 29694914 | 2018 | The origin of GSKIP, a multifaceted regulatory factor in the mammalian Wnt pathway. | 6 |
| 29694914 | 2018 | The origin of GSKIP, a multifaceted regulatory factor in the mammalian Wnt pathway. | 6 |
| 27484798 | 2016 | The 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. | 20 |
| 27484798 | 2016 | The 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. | 20 |
| 26280900 | 2015 | Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies. | 51 |
| 26280900 | 2015 | Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies. | 51 |
| 21328310 | 2011 | Prediction of the binding mode between GSK3β and a peptide derived from GSKIP using molecular dynamics simulation. | 6 |
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-(gsk3-beta-interaction-protein)
