DEF6

Official Full Name

DEF6 guanine nucleotide exchange factor

Organism

Homo sapiens

GeneID

50619

Background

DEF6, or IBP, is a guanine nucleotide exchange factor (GEF) for RAC (MIM 602048) and CDC42 (MIM 116952) that is highly expressed in B and T cells (Gupta et al., 2003 [PubMed 12923183]).[supplied by OMIM, Mar 2008]

Synonyms

IBP; SLAT; IMD87; SWAP70L;

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Detailed Information

In the intricate tapestry of gene expression, certain genes play pivotal roles in regulating cellular processes and development. One such gene is Def6, which stands for differentially expressed in FDCP 6 homolog. This gene has garnered significant attention for its involvement in various physiological and pathological processes.

Function of Def6

Def6 is a member of the F-box protein family, which is characterized by a conserved F-box motif. F-box proteins are known to be components of the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex, which is involved in the ubiquitination and degradation of target proteins. Def6, in particular, has been shown to play a crucial role in regulating the stability and function of various signaling proteins.

Regulation of Def6

The expression of Def6 is tightly controlled at the transcriptional level. Several transcription factors, such as Myc and NF-κB, have been identified as regulators of Def6 gene expression. These factors can bind to the promoter region of the Def6 gene, altering its transcriptional activity. Additionally, post-translational modifications, such as phosphorylation and acetylation, can modulate the function and stability of Def6 protein.

Implications of Def6 in Cell Signaling and Development:

Apoptosis: Def6 has been shown to be involved in the regulation of apoptosis, or programmed cell death. It interacts with pro-apoptotic proteins, such as Bax and Bak, and promotes their ubiquitination and degradation. Consequently, Def6 deficiency leads to increased apoptosis, highlighting its role in maintaining cellular viability.

Inflammation: Def6 also plays a crucial role in regulating inflammation. It interacts with NF-κB, a key transcription factor involved in inflammation, and promotes its degradation. This effectively reduces the production of inflammatory cytokines and mitigates inflammation.

Development: During development, Def6 is essential for the proper differentiation and function of various cell types. Its involvement has been demonstrated in the development of neural cells, where it regulates the stability of neurotransmitter receptors. Additionally, Def6 is required for the differentiation of muscle cells and the regulation of muscle contraction.

Cancer: Given its role in regulating apoptosis and inflammation, Def6 has also been implicated in cancer development. Its expression is often altered in various cancer types, and its dysregulation can contribute to tumor growth and metastasis. Therefore, Def6 has emerged as a potential therapeutic target for cancer treatment.

Cardiac hypertrophy: The high prevalence of heart failure necessitates the elucidation of the mechanisms underlying pathological cardiac hypertrophy in order to identify useful therapeutic targets. In this context, the present study started with the observation of elevated DEF6 expression levels in hypertrophied myocardium and hypertrophic cardiomyocytes. Our further experiments revealed that DEF6 exacerbates pathological hypertrophy, contractile dysfunction, fibrosis, and prehypertrophic stimulus-induced cardiomyocyte hypertrophy, but does not act under physiological conditions. A subsequent mechanistic study revealed that DEF6 exerts its prohypertrophic effects by directly interacting with and activating RAC1, thereby activating downstream MEK-ERK1/2 signalling.

Figure 1. The role and signaling of DEF6 in cardiac hypertrophy

Def6 is a multifaceted gene that plays a crucial role in regulating cell signaling and development. Its involvement in apoptosis, inflammation, development, and cancer highlights its significance in maintaining cellular homeostasis and preventing pathological conditions. Further research on Def6 will undoubtedly uncover additional insights into its function and regulation, offering novel therapeutic strategies for treating diseases associated with its dysregulation.

References:

Sun Y, Xu C, Jiang Z, Jiang X. DEF6(differentially exprehomolog) exacerbates pathological cardiac hypertrophy via RAC1. Cell Death Dis. 2023;14(7):483. Published 2023 Jul 31. doi:10.1038/s41419-023-05948-0
Binder N, Miller C, Yoshida M, et al. Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption. J Immunol. 2017;198(9):3436-3447. doi:10.4049/jimmunol.1601716

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