Dedicator of cytokinesis protein 11 (DOCK11)

Dedicator of cytokinesis protein 11

Dedicator of cytokinesis protein 11 (DOCK11) known as Zizimin2.

It is is a large (~240 kDa) protein encoded in the human by the DOCK11 gene, involved in intracellular signalling networks.

It is a member of the DOCK-D subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G-proteins. 

Dock11 activates the small G protein Cdc42.

DOCK11 gene location chromosome X.

Dock11 is highly expressed in germinal center B lymphocytes, and in the spleen, thymus, bone marrow and in peripheral blood lymphocytes. 

Dock11 is expressed at lower levels in fibroblasts, myoblasts and neuroblastoma cells. 

Dock11 mRNA has also been detected in the pars intermedia.

It shares the highest level of sequence identity with Dock9. 

Dock11 may interact with membrane phospholipids, may be involved in its recruitment to the plasma membrane, 

Regulates signaling pathways that control diverse cellular functions including morphology, migration, endocytosis and cell cycle progression. 

Gene expression studies have suggested that Dock11 may have a role in the development of pituitary and testicular tumors.

Hemizygous DOCK11 mutations in humans are associated with early-onset and severe autoimmunity. 

A reduction in DOCK11 expression was observed in patients presented with early-onset autoimmunity, including cytopenia, systemic lupus erythematosus, skin, and digestive manifestations. 

Platelets and lymphocytes exhibited abnormal ultrastructural morphology and spreading as well as impaired CDC42 activity. 

Cells exhibit aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. 

A DOCK11 knock-down in monocytes-derived dendritic cells and in T cells from healthy controls, demonstrate these abnormal cellular phenotypes. 

Abnormal regulatory T cells (Tregs) phenotype with profoundly reduced FOXP3 and IKZF2 expression is consistent with the autoimmune features developed by the DOCK11-deficient patients. 

DOCK11 deficiency is therefore a new X-linked immune-related actinopathy leading to abnormal actin cytoskeleton remodeling, impaired CDC42 activity and STAT5 activation, and associated with early-onset autoimmunity.

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