| Written | 2016-10 | Christine 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 |
| Identity |
| Alias_names | C14orf129 |
| 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 96364736 and ends at 96387290 bp from pter ( according to hg19-Feb_2009) [Mapping GSKIP.png] |
| Local_order | centromere to telomere. |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| 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). 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 | 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 Predictive of Clinical Outcomes of Human Acute Leukemia. |
| 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 leukemia stem cells in AML |
| Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, Zon LI, Armstrong SA. |
| Science. 2010;327(5973):1650-3 |
| PMID 20339075 |
| Citation |
| This paper should be referenced as such : |
| Christine Bellann-Chantelot, Isabelle Plo |
| GSKIP (GSK3-beta interaction protein) |
| Atlas Genet Cytogenet Oncol Haematol. 2017;21(6):197-199. |
| Free journal version : [ pdf ] [ DOI ] |
| 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 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed Nov 13 21:26:05 CET 2019 |
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