DAB2IP

Official Full Name

DAB2 interacting protein

Organism

Homo sapiens

GeneID

153090

Background

DAB2IP is a Ras (MIM 190020) GTPase-activating protein (GAP) that acts as a tumor suppressor. The DAB2IP gene is inactivated by methylation in prostate and breast cancers (Yano et al., 2005 [PubMed 15386433]).[supplied by OMIM, May 2010]

Synonyms

AIP1; AIP-1; AF9Q34; DIP1/2;

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Detailed Information

DAB2IP, initially identified as a binding partner of Disabled-2 (DAB2), belongs to the RAS GTPase-activating protein (RAS-GAP) family. Over the past decade, research efforts have illuminated its multifaceted functions, ranging from tumor suppression and apoptosis regulation to its involvement in cellular migration, invasion, and epithelial-mesenchymal transition (EMT).

The Structure of DAB2IP

The DAB2IP protein is structurally diverse and composed of several distinct domains that enable its multifunctional role in the cell. The N-terminal domain of DAB2IP contains a bipartite nuclear localization signal (NLS) that facilitates the nuclear import of the protein. This domain is also responsible for binding to the transcription factor CREB1, which is involved in the regulation of gene expression. The central region of DAB2IP contains a sequence similarity domain (SSD), which is involved in protein-protein interactions and is essential for the recruitment of co-activators and the activation of transcription factors. The C-terminal domain of DAB2IP contains a leucine-rich repeat (LRR) region, which is found in many proteins involved in cell signaling and adhesion. This domain mediates interactions with other cellular components, such as integrins and cytoskeletal proteins, playing a role in cell migration and motility. Additionally, the C-terminal region contains a conserved domain known as the PDZ domain, which is involved in the regulation of cell signaling pathways and protein trafficking.

DAB2IP Participation in EMT Regulation

The DAB2IP gene plays a significant role in the epithelial-mesenchymal transition (EMT) process, which is a crucial cellular phenomenon involved in tissue development, repair, and disease progression, including cancer metastasis. EMT occurs when epithelial cells acquire migratory and invasive properties similar to mesenchymal cells. DAB2IP participates in EMT regulation through multiple mechanisms. The N-terminal domain of DAB2IP interacts with transcription factors such as Snail, a well-known regulator of EMT. This interaction promotes the transcription of genes involved in cell migration, invasion, and fibrosis. In the central region, the SSD domain interacts with co-activators and transcription factors, enhancing their activity and leading to the expression of EMT-related genes.

The C-terminal domain of DAB2IP contains a leucine-rich repeat (LRR) region that interacts with cytoskeletal proteins and regulators, modulating cell motility and invasion. Additionally, the PDZ domain in the C-terminal region interacts with cell adhesion molecules, contributing to the loss of cell-cell junctions and the disruption of epithelial integrity during EMT.

DAB2IP also serves as a negative regulator of EMT, counterbalancing the expression of EMT-promoting genes. Knockdown or mutation of DAB2IP can lead to increased EMT activity, resulting in enhanced cell migration, invasion, and fibrosis. In contrast, overexpression of DAB2IP can suppress EMT and inhibit cancer cell metastasis.

DAB2IP Inhibits RAS-dependent Signaling

The DAB2IP gene plays a crucial role in inhibiting RAS-dependent signal transduction pathways. DAB2IP functions as a negative regulator of RAS signaling by interacting with key components of the pathway. It directly binds to the GTP-bound form of RAS proteins, preventing them from binding to their effector proteins and transmitting signals. Additionally, DAB2IP can interact with RAS-associated proteins, such as GDP dissociation inhibitor (GDI), further impeding RAS signaling.

In the nucleus, DAB2IP can modulate the activity of transcription factors that are downstream of RAS, such as AP-1 and CREB, by influencing their DNA binding and transcriptional activity. This results in the reduced expression of RAS-regulated genes involved in cell proliferation, invasion, and angiogenesis.

The leucine-rich repeat (LRR) and PDZ domains in the C-terminal region of DAB2IP contribute to its inhibitory function by interacting with cytoskeletal proteins and cell adhesion molecules, respectively. These interactions disrupt the activation of RAS-dependent signaling cascades and prevent the formation of focal adhesions, which are essential for cell migration and invasion.

Figure 1. DAB2IP inhibits RAS-dependent signaling.

References:

Wang J, Zhu X, Hu J, He G, Li X, Wu P et al. The positive feedback between Snail and DAB2IP regulates EMT, invasion and metastasis in colorectal cancer. Oncotarget 2015; 6:27427–27439.
Yu L, Tumati V, Tseng S-F, Hsu F-M, Kim DN, Hong D et al. DAB2IP regulates autophagy in prostate cancer in response to combined treatment of radiation and a DNA-PKcs inhibitor.Neoplasia 2012; 14: 1203–1212.
hen H, Tu SW, Hsieh JT. Down-regulation of human DAB2IP gene expression mediated by polycomb Ezh2 complex and histone deacetylase in prostate cancer. J Biol Chem 2005; 280:22437–22444.

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