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ANKHD1 (ankyrin repeat and KH domain containing 1)

Written2015-03Joao Agostinho Machado-Neto, Fabiola Traina
Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas (JAMN, FT), Department of Internal Medicine, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto (FT), Sao Paulo, Brazil.;

Abstract ANKHD1 is differentially expressed in human cancers, and potentially regulates multiple cellular functions and participates as a scaffold for protein-protein interactions through its ankyrin-repeat domains. Recently, studies have indicated that ANKHD1 is involved in the regulation of important biological process that participate in the malignant phenotype, including cell cycle progression, proliferation, clonogenicity and migration. The present review on ANKHD1 contains data on DNA/RNA, protein encoded and where the gene is implicated.

Keywords ANKHD1; Cell cycle; Cell proliferation; Migration; Cancer

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HGNC Alias symbMASK
LocusID (NCBI) 54882
Atlas_Id 46476
Location 5q31.3  [Link to chromosome band 5q31]
Location_base_pair Starts at 140401833 and ends at 140472477 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping ANKHD1.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ANKHD1 (5q31.3)::ANKHD1 (5q31.3)ANKHD1 (5q31.3)::CYSTM1 (5q31.3)ANKHD1 (5q31.3)::EIF4EBP3 (5q31.3)
ANKHD1 (5q31.3)::HMGXB4 (22q12.3)ANKHD1 (5q31.3)::PCDH1 (5q31.3)ANKHD1 (5q31.3)::TIAM2 (6q25.3)
CCDC80 (3q13.2)::ANKHD1 (5q31.3)ITGAV (2q32.1)::ANKHD1 (5q31.3)PCDHA11 (5q31.3)::ANKHD1 (5q31.3)
PIK3C2B (1q32.1)::ANKHD1 (5q31.3)SYT14 (1q32.2)::ANKHD1 (5q31.3)TMCC1 (3q22.1)::ANKHD1 (5q31.3)
VPS54 (2p14)::ANKHD1 (5q31.3)


Description The entire ANKHD1 gene is about 147 Kb (start: 139781399 and end: 139929163 bp; orientation: plus strand). The ANKHD1 gene encodes for 4 transcript variants. The transcript variant 1 (start: 139781399 and end: 139919441 bp; orientation: plus strand; 34 exons; mRNA: 8233 bp) is the longest transcript and encodes the isoform 1 (2542 aa protein). The transcript variant 2 (start: 139781399 and end: 139852062 bp; orientation: plus strand; 11 exons; mRNA: 2161 bp) uses an alternate in-frame splice site in the 5` coding region, lacks several exons, uses an alternate 3` terminal exon and encodes the isoform 2, which is shorter and presents a distinct C-terminus compared to isoform 1 (616 aa protein). Transcript variant 3 (start: 139781399 and end: 139852062 bp; orientation: plus strand; 11 exons; mRNA: 2194 bp) lacks several exons, uses an alternate 3` terminal exon and encodes the isoform 3 that also has a distinct C-terminus compared to isoform 1 (627 aa protein). Transcrit variant 4 (start: 139781399 and end: 139852062 bp; orientation: plus strand; 10 exons, mRNA: 2084 bp) also lacks several exons, uses an alternate 3` terminal exon, encodes the isoform 4 that has a distinct C-terminus compared to isoform 1 and is the shortest of all isoforms (581 aa protein). Additionally, ANKHD1-EIF4EBP3 is a readthrough transcript involving ANKHD1 and EIF4EBP3 genes, which encodes a protein that contains multiple ankyrin repeats, single KH-domain and a C-terminus with a portion from the EIF4EBP3 gene (start: 139781399 and end: 139929163 bp; orientation: plus strand; 36 exons, mRNA: 8349 bp; protein: 2617 aa). Data searched at GenBank NCBI ( and UCSC Genome Browser (


Description The ANKHD1 protein has 4 isoforms. Isoforms 2, 3 and 4 are smaller and less characterized than isoform 1. Isoform 1 of ANKHD1 protein consists of 2542 amino acids with a molecular weight of 270 kDa, has 20 ankyrin repeats distributed in two blocks and a K homology (KH) domain in the C-terminal region. The schematic representation of ANKHD1 protein (isoform 1) is illustrated in Figure 1.
Expression Ubiquitous.
Localisation ANKHD1 is predominantly found in the cytoplasm (Figure 2).
Function The ANKHD1 protein contains 20 ankyrin repeats, which are highly conserved structures. The presence of ankyrin repeats domains suggests that this protein integrates multiple signaling pathways and participates as scaffold for protein-protein interactions (Jernigan and Bordenstein, 2015). A large part of the knowledge regarding the functions of ANKHD1 was obtained by experiments using its orthologous protein Mask (multiple ankyrin repeats single KH domain). In Drosophila, Mask acts in the signal transduction pathway mediated by Cws (Corkscrew; orthologous of SHP2) (Smith, et al., 2002), participates in the Hippo signaling pathway activation through its association with Yki (Yorkie, orthologous of YAP1) (Sidor, et al., 2013, Sansores-Garcia, et al., 2013) and potentially regulates Hop signaling pathway (Hopscotch, orthologous of JAK) (Muller, et al., 2005). In humans, ANKHD1 associates with SHP2, however the biologic consequence of this protein interaction remains indeterminate (Traina, et al., 2006). ANKHD1 and YAP1 interaction has also been confirmed in human cells (HEK293 and DU145 cells) and modulates the Hippo signaling pathway activation, proliferation and cell cycle progression (Sidor, et al., 2013, Sansores-Garcia, et al., 2013, Machado-Neto, et al., 2014). ANKHD1 interacts with SIVA and modulates the microtubule dynamics, cell proliferation and migration of human leukemia cells (Machado-Neto, et al., 2015). In addition, ANKHD1 modulates p21 (CDKN1A) expression and cell cycle progression in multiple myeloma cells (Dhyani, et al., 2015, Dhyani, et al., 2012). In NT2 cells, inhibition of the small isoform of ANKHD1 that lacks the KH domain (also designed as VBARP; isoform 3) triggered caspase-3/7 activation (Miles, et al., 2005), however no similar effect on apoptosis was observed in the other cell lines inhibited for all other ANKHD1 isoforms (Machado-Neto, et al., 2014, Machado-Neto, et al., 2015, Dhyani, et al., 2012). A potential model for ANKHD1 cellular functions and protein interactions is summarized in Figure 3.
Homology ANKHD1 shares high homology with ANKRD17 (ankyrin repeat domain 17), both orthologous proteins to Mask protein from Drosophila. ANKHD1 also shares high homology among different species (Table 1).


Somatic Recurrent mutations in the ANKHD1 gene are rare, 180 substitution missense, 13 substitution nonsense, 58 substitution synonymous, 1 insertion frameshift and 1 deletion frameshift mutations are reported in COSMIC (Catalogue of somatic mutations in cancer;

Implicated in

Entity Leukemia
Note ANKHD1 was reported as highly expressed in leukemia cell lines and in primary bone marrow samples from patients with acute myeloid leukemia and acute lymphoid leukemia (Traina, et al., 2006). Interestingly, ANKHD1 silencing reduced cell proliferation, clonogenicity, migration and tumorigenesis of leukemia cells (Machado-Neto, et al., 2015).
Entity Multiple myeloma
Disease Multiple myeloma cell lines and primary plasma cells from myeloma multiple patients presented a high expression of ANKHD1 (Dhyani, et al., 2012). In multiple myeloma cell lines, ANKHD1 inhibition resulted in a delay in cell cycle progression and lower cell proliferation, clonal growth, migration and tumor formation (Dhyani, et al., 2015, Dhyani, et al., 2012).
Entity Prostate cancer
Note High expression of ANKHD1 was observed in prostate cancer cell lines (Machado-Neto, et al., 2014). Using the siRNA approach, ANKHD1 silencing reduced proliferation, tumor formation, and cell cycle progression in prostate cancer cells (Machado-Neto, et al., 2014).
Entity Breast cancer
Prognosis In two independent cohorts of breast cancer patients, high expression of ANKHD1 was associated with worsened outcomes (Sansores-Garcia, et al., 2013).

To be noted

Although ANKHD1 presents high homology with ANKRD17 (both orthologous proteins of Mask), the Ankrd17 knockout mice presents embryonic lethality (Hou, et al., 2009), indicating that these proteins do not play redundant functions. Another interesting point is that, accordingly to current data, ANKHD1 participates in cell proliferation and cell cycle progression in different neoplastic cells; however the ANKHD1-interacting proteins appear to vary, depending on the cellular context.


ANKHD1 regulates cell cycle progression and proliferation in multiple myeloma cells
Dhyani A, Duarte AS, Machado-Neto JA, Favaro P, Ortega MM, Olalla Saad ST
FEBS Lett 2012 Dec 14;586(24):4311-8
PMID 23142581
ANKHD1 represses p21 (WAF1/CIP1) promoter and promotes multiple myeloma cell growth
Dhyani A, Machado-Neto JA, Favaro P, Saad ST
Eur J Cancer 2015 Jan;51(2):252-9
PMID 25483783
Ankrd17, an ubiquitously expressed ankyrin factor, is essential for the vascular integrity during embryogenesis
Hou SC, Chan LW, Chou YC, Su CY, Chen X, Shih YL, Tsai PC, Shen CK, Yan YT
FEBS Lett 2009 Sep 3;583(17):2765-71
PMID 19619540
Tandem-repeat protein domains across the tree of life
Jernigan KK, Bordenstein SR
PeerJ 2015 Jan 13;3:e732
PMID 25653910
Identification of JAK/STAT signalling components by genome-wide RNA interference
Müller P, Kuttenkeuler D, Gesellchen V, Zeidler MP, Boutros M
Nature 2005 Aug 11;436(7052):871-5
PMID 16094372
ANKHD1 silencing inhibits Stathmin 1 activity, cell proliferation and migration of leukemia cells
Machado-Neto JA, Lazarini M, Favaro P, de Melo Campos P, Scopim-Ribeiro R, Franchi GC Junior, Nowill AE, Lima PR, Costa FF, Benichou S, Olalla Saad ST, Traina F
Biochim Biophys Acta 2015 Mar;1853(3):583-593
PMID 25523139
Molecular and functional characterization of a novel splice variant of ANKHD1 that lacks the KH domain and its role in cell survival and apoptosis
Miles MC, Janket ML, Wheeler ED, Chattopadhyay A, Majumder B, Dericco J, Schafer EA, Ayyavoo V
FEBS J 2005 Aug;272(16):4091-102
PMID 16098192
Mask is required for the activity of the Hippo pathway effector Yki/YAP
Sansores-Garcia L, Atkins M, Moya IM, Shahmoradgoli M, Tao C, Mills GB, Halder G
Curr Biol 2013 Feb 4;23(3):229-35
PMID 23333314
Mask proteins are cofactors of Yorkie/YAP in the Hippo pathway
Sidor CM, Brain R, Thompson BJ
Curr Biol 2013 Feb 4;23(3):223-8
PMID 23333315
MASK, a large ankyrin repeat and KH domain-containing protein involved in Drosophila receptor tyrosine kinase signaling
Smith RK, Carroll PM, Allard JD, Simon MA
Development 2002 Jan;129(1):71-82
PMID 11782402
ANKHD1, ankyrin repeat and KH domain containing 1, is overexpressed in acute leukemias and is associated with SHP2 in K562 cells
Traina F, Favaro PM, Medina Sde S, Duarte Ada S, Winnischofer SM, Costa FF, Saad ST
Biochim Biophys Acta 2006 Sep;1762(9):828-34
PMID 16956752


This paper should be referenced as such :
Joao Agostinho Machado-Neto, Fabiola Traina
ANKHD1 (ankyrin repeat and KH domain containing 1)
Atlas Genet Cytogenet Oncol Haematol. 2016;20(3):98-101.
Free journal version : [ pdf ]   [ DOI ]

External links

HGNC (Hugo)ANKHD1   24714
Entrez_Gene (NCBI)ANKHD1    ankyrin repeat and KH domain containing 1
AliasesMASK; MASK1; PP2500; VBARP
GeneCards (Weizmann)ANKHD1
Ensembl hg19 (Hinxton)ENSG00000131503 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000131503 [Gene_View]  ENSG00000131503 [Sequence]  chr5:140401833-140472477 [Contig_View]  ANKHD1 [Vega]
ICGC DataPortalENSG00000131503
Genatlas (Paris)ANKHD1
SOURCE (Princeton)ANKHD1
Genetics Home Reference (NIH)ANKHD1
Genomic and cartography
GoldenPath hg38 (UCSC)ANKHD1  -     chr5:140401833-140472477 +  5q31.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ANKHD1  -     5q31.3   [Description]    (hg19-Feb_2009)
GoldenPathANKHD1 - 5q31.3 [CytoView hg19]  ANKHD1 - 5q31.3 [CytoView hg38]
Genome Data Viewer NCBIANKHD1 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AF217646 AF258557 AF521882 AI675547 AI870943
RefSeq transcript (Entrez)NM_001197030 NM_017747 NM_017978 NM_024668
Consensus coding sequences : CCDS (NCBI)ANKHD1
Gene ExpressionANKHD1 [ NCBI-GEO ]   ANKHD1 [ EBI - ARRAY_EXPRESS ]   ANKHD1 [ SEEK ]   ANKHD1 [ MEM ]
Gene Expression Viewer (FireBrowse)ANKHD1 [ Firebrowse - Broad ]
GenevisibleExpression of ANKHD1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)54882
GTEX Portal (Tissue expression)ANKHD1
Human Protein AtlasENSG00000131503-ANKHD1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)ANKHD1
Human Protein Atlas [tissue]ENSG00000131503-ANKHD1 [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed63 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:12:30 CEST 2021

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