ANKHD1 (ankyrin repeat and KH domain containing 1)

2015-03-01   Joao Agostinho Machado-Neto , Fabiola Traina 

Identity

HGNC
LOCATION
5q31.3
LOCUSID
ALIAS
MASK,MASK1,PP2500,VBARP
FUSION GENES

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.

DNA/RNA

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 (http://www.ncbi.nlm.nih.gov/genbank/) and UCSC Genome Browser (https://genome.ucsc.edu/).

Proteins

Atlas Image

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.
Atlas Image

Localisation

ANKHD1 is predominantly found in the cytoplasm (Figure 2).
Atlas Image

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.
Atlas Image

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).

Mutations

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; http://cancer.sanger.ac.uk/cancergenome/projects/cosmic).

Implicated in

Entity name
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 name
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 name
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 name
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).

Bibliography

Pubmed IDLast YearTitleAuthors
231425812012ANKHD1 regulates cell cycle progression and proliferation in multiple myeloma cells.Dhyani A et al
254837832015ANKHD1 represses p21 (WAF1/CIP1) promoter and promotes multiple myeloma cell growth.Dhyani A et al
196195402009Ankrd17, an ubiquitously expressed ankyrin factor, is essential for the vascular integrity during embryogenesis.Hou SC et al
256539102015Tandem-repeat protein domains across the tree of life.Jernigan KK et al
160943722005Identification of JAK/STAT signalling components by genome-wide RNA interference.Müller P et al
255231392015ANKHD1 silencing inhibits Stathmin 1 activity, cell proliferation and migration of leukemia cells.Machado-Neto JA et al
160981922005Molecular 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 et al
233333142013Mask is required for the activity of the Hippo pathway effector Yki/YAP.Sansores-Garcia L et al
233333152013Mask proteins are cofactors of Yorkie/YAP in the Hippo pathway.Sidor CM et al
117824022002MASK, a large ankyrin repeat and KH domain-containing protein involved in Drosophila receptor tyrosine kinase signaling.Smith RK et al
169567522006ANKHD1, ankyrin repeat and KH domain containing 1, is overexpressed in acute leukemias and is associated with SHP2 in K562 cells.Traina F et al

Other Information

Locus ID:

NCBI: 54882
MIM: 610500
HGNC: 24714
Ensembl: ENSG00000131503

Variants:

dbSNP: 54882
ClinVar: 54882
TCGA: ENSG00000131503
COSMIC: ANKHD1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000131503ENST00000246149H3BLS9
ENSG00000131503ENST00000297183A0A0A0MQZ8
ENSG00000131503ENST00000360839Q8IWZ3
ENSG00000131503ENST00000394722Q8IWZ3
ENSG00000131503ENST00000394723Q8IWZ3
ENSG00000131503ENST00000412116H7C2F5
ENSG00000131503ENST00000421134E9PDP5
ENSG00000131503ENST00000421706H7C2E1
ENSG00000131503ENST00000431508H0Y4P6
ENSG00000131503ENST00000432301H0Y7Y3
ENSG00000131503ENST00000433049H0Y472
ENSG00000131503ENST00000435794H0Y785
ENSG00000131503ENST00000511151D6RHC4
ENSG00000131503ENST00000616482Q8IWZ3

Expression (GTEx)

0
10
20
30
40
50
60
70

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
247269152014ANKHD1, a novel component of the Hippo signaling pathway, promotes YAP1 activation and cell cycle progression in prostate cancer cells.19
169567522006ANKHD1, ankyrin repeat and KH domain containing 1, is overexpressed in acute leukemias and is associated with SHP2 in K562 cells.12
254837832015ANKHD1 represses p21 (WAF1/CIP1) promoter and promotes multiple myeloma cell growth.10
255231392015ANKHD1 silencing inhibits Stathmin 1 activity, cell proliferation and migration of leukemia cells.10
231425812012ANKHD1 regulates cell cycle progression and proliferation in multiple myeloma cells.9
306469492019ANKHD1 is required for SMYD3 to promote tumor metastasis in hepatocellular carcinoma.9
160981922005Molecular and functional characterization of a novel splice variant of ANKHD1 that lacks the KH domain and its role in cell survival and apoptosis.7
296955082018Ankyrin repeat and single KH domain 1 (ANKHD1) drives renal cancer cell proliferation via binding to and altering a subset of miRNAs.5
162975702005Characterisation of a new splice variant of MASK-BP3(ARF) and MASK human genes, and their expression patterns during haematopoietic cell differentiation.0

Citation

Joao Agostinho Machado-Neto ; Fabiola Traina

ANKHD1 (ankyrin repeat and KH domain containing 1)

Atlas Genet Cytogenet Oncol Haematol. 2015-03-01

Online version: http://atlasgeneticsoncology.org/gene/46476/ankhd1