Dock3

Dock3 ( D edicator o f c yto k inesis 3), also known as MOCA ( m odifier o f c ell a dhesion) and PBP ( p resenilin- b inding p rotein), is a large (~180 kDa) is_associated_with::protein involved in is_associated_with::intracellular signalling networks. It is a member of the DOCK-B subfamily of the DOCK family of is_associated_with::guanine nucleotide exchange factors (GEFs) which function as activators of small is_associated_with::G proteins. Dock3 specifically activates the small G protein Rac.

Discovery
Dock3 was originally discovered in a screen for proteins that bind is_associated_with::presenilin (a is_associated_with::transmembrane protein which is mutated in early onset is_associated_with::Alzheimer's disease). Dock3 is specifically expressed in is_associated_with::neurones (primarily in the is_associated_with::cerebral cortex and is_associated_with::hippocampus).

Structure and function
Dock3 is part of a large class of proteins (GEFs) which contibrute to cellular signalling events by activating small G proteins. In their resting state G proteins are bound to is_associated_with::Guanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding of is_associated_with::guanosine triphosphate (GTP). GEFs activate G proteins by promoting this nucleotide exchange.

Dock3 exhibits the same domain arrangement as is_associated_with::Dock180 (a member of the DOCK-A subfamily and the archetypal member of the DOCK family) and these proteins share a considerable (40%) degree of is_associated_with::sequence similarity.

Regulation of Dock3 activity
Since Dock3 shares the same domain arrangement as Dock180 it is predicted to have a similar array of binding partners, although this has yet to be demonstrated. It contains an is_associated_with::N-terminal is_associated_with::SH3 domain, which in Dock180 binds ELMO (a family of is_associated_with::adaptor proteins which mediate recruitment and efficient GEF activity of Dock180), and a is_associated_with::C-terminal is_associated_with::proline-rich region which, in Dock180, binds the adaptor protein CRK.

Signalling downstream of Dock3
Dock3 GEF activity is directed specifically at is_associated_with::Rac1. Dock3 has not been shown to interact with is_associated_with::Rac3, another Rac protein which is expressed in neuronal cells, and this may be because Rac3 is primarily located in the perinuclear region. In fact, Rac1 and Rac3 appear to have distinct and antagonistic roles in these cells. Dock3-mediated Rac1 activation promotes reorganisation of the is_associated_with::cytoskeleton in is_associated_with::SH-SY5Y is_associated_with::neuroblastoma cells and primary cortical neurones as well as morphological changes in is_associated_with::fibroblasts. It has also been shown to regulate is_associated_with::neurite outgrowth and cell-cell adhesion in is_associated_with::B103 and is_associated_with::PC12 cells.

Dock3 in neurological disorders
The first indication that Dock3 might be involved in neurological disorders came when Dock3 was shown to bind to presenilin, a transmembrane enzyme involved in the generation of is_associated_with::beta amyloid (Aβ), accumulation of which is an important step in the development of Alzheimer's disease. Dock3 has been shown to undergo redistribution and association with is_associated_with::neurofibrillary tangles in brain samples from Alzheimers patients. A mutation in Dock3 was also identified in a family displaying a is_associated_with::phenotype resembling is_associated_with::attention-deficit hyperactivity disorder (ADHD).