DCHS1

Official Full Name

dachsous cadherin-related 1

Organism

Homo sapiens

GeneID

8642

Background

This gene is a member of the cadherin superfamily whose members encode calcium-dependent cell-cell adhesion molecules. The encoded protein has a signal peptide, 27 cadherin repeat domains and a unique cytoplasmic region. This particular cadherin family member is expressed in fibroblasts but not in melanocytes or keratinocytes. The cell-cell adhesion of fibroblasts is thought to be necessary for wound healing. [provided by RefSeq, Jul 2008]

Synonyms

FIB1; MVP2; CDH19; CDH25; CDHR6; MMVP2; PCDH16; VMLDS1;

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Detailed Information

The Dachsous cadherin-related 1 (DChs1) gene is a crucial player in several cellular processes, including cell migration, cell signaling, and tissue patterning.

Structure of DChs1 And Its Role

DChs1 gene is a highly conserved gene that belongs to the protocadherin family, which is characterized by encoding cell adhesion proteins crucial for tissue development and maintenance. The DChs1 protein exhibits a distinct structural arrangement, consisting of several distinct domains that contribute to its functional versatility.

The primary structure of DChs1 consists of a signal peptide, followed by a large extracellular domain (ECD) that is responsible for cell-cell adhesion. The ECD shares similarities with other cadherin proteins, including a classic cadherin repeats (CR) domain, which is characterized by multiple cysteine-rich motifs. These motifs contribute to the formation of disulfide bonds, stabilizing the protein and facilitating adhesive interactions with neighboring cells.

In addition to the CR domain, the ECD of DChs1 contains a classic cadherin-type calcium-binding domain (CaB) that binds calcium ions, regulating cell-cell adhesion and signaling pathways. Furthermore, the ECD exhibits a unique Dachsous domain, which is absent in other cadherin family members and is thought to contribute to the specificity of DChs1's adhesive properties.

The cytoplasmic domain of DChs1 extends into the cell interior, where it interacts with the actin cytoskeleton and participating in cellular processes such as motility, polarization, and differentiation. The cytoplasmic domain also contains several phosphorylation sites, which are susceptible to regulatory signals and modify the protein's function accordingly.

Signaling Pathway and Targeted Therapy

The signaling pathway of DCHS1 involves its interaction with other proteins, leading to the activation of various signaling cascades. For instance, DCHS1 can bind to fibroblast growth factors (FGFs) and activate the FGF signaling pathway. This pathway is crucial for cell survival, proliferation, and differentiation, and its activation can promote tumorigenesis and fibrosis.

Targeted therapy for DCHS1 involves the inhibition of its expression or function, thereby blocking its involvement in disease pathogenesis. several strategies have been proposed for the development of DCHS1-targeted therapeutics, including small molecules, antibodies, and siRNA. For instance, specific antibodies targeting DCHS1 can be used to block its interaction with other proteins and thereby inhibit its signaling function. Similarly, small molecules that bind to DCHS1 and prevent its activation can be developed as therapeutic agents.

DChs1 in Neurological Disorders

Dachsous cadherin-related 1 (DChs1) gene has been implicated in various neurological disorders, contributing to the development and progression of diseases such as Alzheimer's disease, Parkinson's disease, and epilepsy. Abnormalities in the DChs1 gene can lead to defects in neuronal function, structure, and synaptic plasticity, ultimately resulting in neurodegeneration.

In Alzheimer's disease, mutations in the DChs1 gene have been associated with increased production of amyloid beta (Aβ) peptides, which are known to contribute to the formation of plaques characteristic of the disease. Furthermore, DChs1 plays a crucial role in the regulation of tau protein phosphorylation, and its dysfunction can lead to the accumulation of hyperphosphorylated tau, a hallmark of Alzheimer's pathology.

In Parkinson's disease, mutations in the DChs1 gene have been linked to decreased dopamine production and impairments in mitochondrial function, resulting in oxidative stress and cell death in dopaminergic neurons. Additionally, DChs1 interacts with the Parkinson's-associated protein LRRK2, suggesting a possible role in the pathogenesis of this disease.

References:

Medina, Elliot et al. "Structure of the planar cell polarity cadherins Fat4 and Dachsous1." Nature communications vol. 14,1 891. 16 Feb. 2023, doi:10.1038/s41467-023-36435-x
Kubelt, Carolin et al. "Insights into Gene Regulation under Temozolomide-Promoted Cellular Dormancy and Its Connection to Stemness in Human Glioblastoma." Cells vol. 12,11 1491. 27 May. 2023, doi:10.3390/cells12111491

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