ASAP1 (ArfGAP with SH3 domain, ankyrin repeat and PH domain 1)

2012-02-01   Hisataka Sabe , Yasuhito Onodera , Ari Hashimoto , Shigeru Hashimoto 

Hokkaido University Graduate School of Medicine, Department of Molecular Biology, Sapporo, Japan

Identity

HGNC
LOCATION
8q24.21
IMAGE
Atlas Image
LEGEND
The ASAP1 gene maps on chromosome 8, at 8q24.1-q24.2 according to Entrez Gene (adapted from GeneCards).
LOCUSID
ALIAS
AMAP1,CENTB4,DDEF1,PAG2,PAP,ZG14P
FUSION GENES

DNA/RNA

Atlas Image

Description

The ASAP1 locus spans 391,75 kb, on the minus strand of chromosome 8 from 131456099 to 131064346.

Transcription

Transcription produces 16 different mRNAs, 12 alternatively spliced variants and 4 unspliced forms.
There are 9 probable alternative promotors, 6 non overlapping alternative last exons and 5 validated alternative polyadenylation sites. The mRNAs appear to differ by truncation of the 5 end, truncation of the 3 end, presence or absence of 15 cassette exons, overlapping exons with different boundaries (NCBI).

Proteins

Expression

Epithelial cells, fibroblasts, macrophages, brain (for references see above), and endothelial cells (Hashimoto et al., 2011). Not determined with the other types of cells.

Localisation

Intracellular tubulovesicular structures and vesicles, plasma membrane protrusions and leading edges, and invadopodia/podosome structures (Hashimoto et al., 2004; Hashimoto et al., 2005; Onodera et al., 2005).

Function

ASAP1 has an ArfGAP zinc-finger domain and exhibits phosphatidylinositol 4,5-bisphosphate-dependent GAP activities for Arf1 and Arf5 but 102- to 103-fold less activity for Arf6 (Brown et al., 1998; Andreev et al., 1999). ASAP1 was shown to enhance cell motility, and this activity was proposed to be mediated by its GAP activity towards Arf1 (Furman et al., 2002). ASAP1 was also shown to associate with focal adhesion kinase (FAK) and contribute to focal adhesion assembly (Liu et al., 2002). Hashimoto et al. (2004 and 2005) have shown that AMAP1 and AMAP2 have the ability to bind stably with GTP-Arf6, but not GDP-Arf6 or other GTP-/GDP-Arf isoforms, in vitro and in vivo. Through this binding, AMAP1 and AMAP2 appear to function as downstream effectors for GTP-Arf6 (Hashimoto et al., 2004; Hashimoto et al., 2005; Onodera et al., 2005). AMAP1 binds to paxillin and cortactin, which are essential components of the invadopodia of MDA-MB-231 breast cancer cells, and acts to recruit these proteins to the sites of Arf6 activation to form invadopodia (Onodera et al., 2005). AMAP1 is hence essential for invasion and metastasis of some breast cancer cells, while AMAP2 is not a component of invadopodia (Onodera et al., 2005; Hashimoto et al., 2006; Nam et al., 2007; Morishige et al., 2008; Sabe et al., 2009). AMAP1 appears to be a useful diagnostic marker as well as therapeutic target of different types of human cancers (see below).

Implicated in

Entity name
Breast cancer
Note
In primary breast cancers, AMAP1 protein, but not AMAP2 protein, is abnormally overexpressed in their significant population in a manner independent of the transcriptional upregulation of the AMAP1 gene, and levels of AMAP1 protein expression correlates well with the malignant phenotypes (Onodera et al., 2005).
Entity name
Melanoma
Note
With the name DDEF1, this gene was identified to be located in an amplified region of chromosome 8q24.12, and the amplification of chromosome 8q in uveal melanomas was found to correlate most strongly with the expression of this gene in melanomas (Ehlers et al., 2005).
Entity name
Colorectal cancer
Note
Protein expression of ASAP1 is upregulated in colorectal cancer cells, and this expression correlates with poor metastasis-free survival and prognosis in colorectal cancer patients (Müller et al., 2010). It is worth noting, on the other hand, that a previous study on the copy number changes at 8q11-24 in colorectal carcinomas showed that although the MYC gene, located at 8q24.12-q24.13, is indeed amplified and correlates with the advanced stages of colorectal carcinoma, the DDEF1 gene was not amplified (Buffart et al., 2005).
Entity name
Prostate cancer
Note
Additional gene copies of ASAP1 were also detected in a large population of primary prostate cancers, and ASAP1 protein staining was found to be elevated in 80% of primary prostate cancers with substantially higher amounts observed in metastatic lesions compared with benign prostate tissue (Lin et al., 2008).
Entity name
Pancreatic ductal adenocarcinoma
Note
DDEF1 gene was found to be frequently amplified, most likely to be oncogenic, in pancreatic ductal adenocarcinomas, accompanied by enhanced expression of this gene (Harada et al., 2009).
Entity name
VEGF- and tumor-induced angiogenesis
Note
AMAP1 protein is highly expressed in endothelial cells upon their treatment with vascular endothelial growth factor (VEGF), and an essential component of VEGF- and tumor-induced angiogenesis, and also choroidal neovascularization (Hashimoto et al., 2011).

Bibliography

Pubmed IDLast YearTitleAuthors
100229201999Identification of a new Pyk2 target protein with Arf-GAP activity.Andreev J et al
98193911998ASAP1, a phospholipid-dependent arf GTPase-activating protein that associates with and is phosphorylated by Src.Brown MT et al
157502082005DNA copy number changes at 8q11-24 in metastasized colorectal cancer.Buffart TE et al
158975552005DDEF1 is located in an amplified region of chromosome 8q and is overexpressed in uveal melanoma.Ehlers JP et al
117730702002DEF-1/ASAP1 is a GTPase-activating protein (GAP) for ARF1 that enhances cell motility through a GAP-dependent mechanism.Furman C et al
190774512009Genome-wide analysis of pancreatic cancer using microarray-based techniques.Harada T et al
218580862011GEP100-Arf6-AMAP1-cortactin pathway frequently used in cancer invasion is activated by VEGFR2 to promote angiogenesis.Hashimoto A et al
164132722005Assays and properties of the ArfGAPs, AMAP1 and AMAP2, in Arf6 function.Hashimoto S et al
100229191999DEF-1, a novel Src SH3 binding protein that promotes adipogenesis in fibroblastic cell lines.King FJ et al
107499322000A new paxillin-binding protein, PAG3/Papalpha/KIAA0400, bearing an ADP-ribosylation factor GTPase-activating protein activity, is involved in paxillin recruitment to focal adhesions and cell migration.Kondo A et al
185196962008ASAP1, a gene at 8q24, is associated with prostate cancer metastasis.Lin D et al
120580762002The association of ASAP1, an ADP ribosylation factor-GTPase activating protein, with focal adhesion kinase contributes to the process of focal adhesion assembly.Liu Y et al
112510772001An ADP-ribosylation factor GTPase-activating protein Git2-short/KIAA0148 is involved in subcellular localization of paxillin and actin cytoskeletal organization.Mazaki Y et al
180842812008GEP100 links epidermal growth factor receptor signalling to Arf6 activation to induce breast cancer invasion.Morishige M et al
201547192010ASAP1 promotes tumor cell motility and invasiveness, stimulates metastasis formation in vivo, and correlates with poor survival in colorectal cancer patients.Müller T et al
172559432007CIN85, a Cbl-interacting protein, is a component of AMAP1-mediated breast cancer invasion machinery.Nam JM et al
157190142005Expression of AMAP1, an ArfGAP, provides novel targets to inhibit breast cancer invasive activities.Onodera Y et al
194164742009The EGFR-GEP100-Arf6-AMAP1 signaling pathway specific to breast cancer invasion and metastasis.Sabe H et al
169043072006ArfGAP family proteins in cell adhesion, migration and tumor invasion.Sabe H et al

Other Information

Locus ID:

NCBI: 50807
MIM: 605953
HGNC: 2720
Ensembl: ENSG00000153317

Variants:

dbSNP: 50807
ClinVar: 50807
TCGA: ENSG00000153317
COSMIC: ASAP1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000153317ENST00000357668A0A0A0MRE5
ENSG00000153317ENST00000518721Q9ULH1
ENSG00000153317ENST00000519483H0YBM4
ENSG00000153317ENST00000520342E5RFD9
ENSG00000153317ENST00000520927E5RHA9
ENSG00000153317ENST00000521075E5RHA9
ENSG00000153317ENST00000521426E5RHD7
ENSG00000153317ENST00000524124H0YBF7
ENSG00000153317ENST00000524299E5RHA9

Expression (GTEx)

0
10
20
30
40
50
60
70
80
90

Pathways

PathwaySourceExternal ID
EndocytosisKEGGko04144
EndocytosisKEGGhsa04144
Fc gamma R-mediated phagocytosisKEGGko04666
Fc gamma R-mediated phagocytosisKEGGhsa04666
Organelle biogenesis and maintenanceREACTOMER-HSA-1852241
Cilium AssemblyREACTOMER-HSA-5617833
Cargo trafficking to the periciliary membraneREACTOMER-HSA-5620920
VxPx cargo-targeting to ciliumREACTOMER-HSA-5620916

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
257746362015Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration.49
186850822008Arf GTPase-activating protein ASAP1 interacts with Rab11 effector FIP3 and regulates pericentrosomal localization of transferrin receptor-positive recycling endosome.46
185196962008ASAP1, a gene at 8q24, is associated with prostate cancer metastasis.44
227340032012Rab5c promotes AMAP1-PRKD2 complex formation to enhance β1 integrin recycling in EGF-induced cancer invasion.44
158975552005DDEF1 is located in an amplified region of chromosome 8q and is overexpressed in uveal melanoma.43
166362902006Targeting AMAP1 and cortactin binding bearing an atypical src homology 3/proline interface for prevention of breast cancer invasion and metastasis.38
184007622008ASAP3 is a focal adhesion-associated Arf GAP that functions in cell migration and invasion.33
190176322009Autoinhibition of Arf GTPase-activating protein activity by the BAR domain in ASAP1.32
201547192010ASAP1 promotes tumor cell motility and invasiveness, stimulates metastasis formation in vivo, and correlates with poor survival in colorectal cancer patients.31
117730702002DEF-1/ASAP1 is a GTPase-activating protein (GAP) for ARF1 that enhances cell motility through a GAP-dependent mechanism.30

Citation

Hisataka Sabe ; Yasuhito Onodera ; Ari Hashimoto ; Shigeru Hashimoto

ASAP1 (ArfGAP with SH3 domain, ankyrin repeat and PH domain 1)

Atlas Genet Cytogenet Oncol Haematol. 2012-02-01

Online version: http://atlasgeneticsoncology.org/gene/44351/asap1