DDEF1

Official Full Name

ArfGAP with SH3 domain, ankyrin repeat and PH domain 1

Organism

Homo sapiens

GeneID

50807

Background

This gene encodes an ADP-ribosylation factor (ARF) GTPase-activating protein. The GTPase-activating activity is stimulated by phosphatidylinositol 4,5-biphosphate (PIP2), and is greater towards ARF1 and ARF5, and lesser for ARF6. This gene maybe involved in regulation of membrane trafficking and cytoskeleton remodeling. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

Synonyms

ASAP1; PAP; PAG2; AMAP1; DDEF1; ZG14P; CENTB4;

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Detailed Information

DDEF1 (Development and Differentiation-Enhancing Factor 1) is a gene that has garnered significant attention for its critical role in regulating development and cell differentiation. DDEF1, also known as Arf-GAP (ASAP1) containing SH3, ankyrin repeat sequences, and a pleckstrin structural domain, is an ADP-ribosylation factor-GTPase-activating protein, which interacts with signaling proteins involved in growth and differentiation (e.g., SRK, FAK, 4,5-bisphosphate phosphatidylinositol, and CRK) interact and regulate actin cytoskeleton remodeling essential for cell motility. Initially identified in a screen for genes that enhance the differentiation of mouse embryonic stem cells (ESCs) into neural precursor cells (NPCs), DDEF1 has since been found to play a pivotal role in various biological processes.

Structure and Expression Pattern of ddef1

The human DDEF1 gene is located on chromosome 10q22.3 and spans approximately 5.6 kb, consisting of 11 exons. The DDEF1 protein is encoded by a transcript of approximately 1.5 kb and is predicted to have a molecular weight of approximately 50 kDa. The expression pattern of DDEF1 varies depending on the organism and tissue type. In mammals, DDEF1 is expressed in various tissues, including the brain, heart, liver, and skeletal muscle, with highest expression levels observed in the developing brain. In Drosophila, DDEF1 is expressed in the developing central nervous system (CNS), while in C. elegans, it is expressed in the intestine and pharynx.

Functional Roles in Development and Cell Differentiation of ddef1

In mammals, DDEF1 is involved in the differentiation of ESCs into NPCs and neurons, as well as in the regulation of neural tube closure and brain development. In Drosophila, DDEF1 is required for the proper differentiation of neural progenitors and glial cells in the CNS, as well as for the regulation of cell proliferation. In C. elegans, DDEF1 is involved in the regulation of intestinal cell differentiation and pharyngeal development.

DDEF1 regulate cell differentiation through various mechanisms. In mammals, DDEF1 interacts with the retinoblastoma protein (Rb) and enhances its phosphorylation, leading to the release of E2F transcription factors and the induction of cell cycle progression. In Drosophila, DDEF1 interacts with the DNA methyltransferase Enhancer of Zeste (EZH2) and represses the expression of several differentiation genes, including the proneural gene achaete-scute complex (ASC). In C. elegans, DDEF1 interacts with the Wnt signaling pathway and regulate the expression of target genes involved in cell differentiation.

DDEF1 and inhibition of cell spreading

Cell motility involves inhibition of cell spreading followed by extension of the peripheral elastic lamellae in the direction of motility, which requires constant remodeling of the actin cytoskeleton and assembly/disassembly of focal adhesions at the leading and trailing edges of cell motility. This requires constant remodeling of the actin cytoskeleton and assembly/disassembly of focal adhesions at the leading and trailing edges of the motile cell, respectively. The DDEF1 protein localizes to newly formed focal complexes at the cell periphery and regulates these periodic changes in cytoskeleton and focal adhesions. Overexpression of DDEF1 protein disrupts the turnover of focal adhesions, thereby preventing cell spreading and promoting cell motility. Thus, oncogenic upregulation of DDEF1 may at least partially explain the increased invasive and metastatic potential of high-grade uveal melanoma.

References:

Ehlers JP, Worley L, Onken MD, Harbour JW. DDEF1 is located in an amplified region of chromosome 8q and is overexpressed in uveal melanoma. Clin Cancer Res. 2005 May 15;11(10):3609-13. doi: 10.1158/1078-0432.CCR-04-1941. PMID: 15897555.
Chen C, Zhao Q, Shao Y, Li Y, Song H, Li G, Zhu L, Lu W, Xu B. A Common Variant of ASAP1 Is Associated with Tuberculosis Susceptibility in the Han Chinese Population. Dis Markers. 2019 Apr 8;2019:7945429. doi: 10.1155/2019/7945429. PMID: 31089398; PMCID: PMC6476032.

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