DCTN1

This gene encodes the largest subunit of dynactin, a macromolecular complex consisting of 10 subunits ranging in size from 22 to 150 kD. Dynactin binds to both microtubules and cytoplasmic dynein. Dynactin is involved in a diverse array of cellular functions, including ER-to-Golgi transport, the centripetal movement of lysosomes and endosomes, spindle formation, chromosome movement, nuclear positioning, and axonogenesis. This subunit interacts with dynein intermediate chain by its domains directly binding to dynein and binds to microtubules via a highly conserved glycine-rich cytoskeleton-associated protein (CAP-Gly) domain in its N-terminus. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. Mutations in this gene cause distal hereditary motor neuronopathy type VIIB (HMN7B) which is also known as distal spinal and bulbar muscular atrophy (dSBMA). [provided by RefSeq, Oct 2008]

Dynactin Subunit 1

Plays a key role in dynein-mediated retrograde transport of vesicles and organelles along microtubules by recruiting and tethering dynein to microtubules. Binds to both dynein and microtubules providing a link between specific cargos, microtubules and dynein. Essential for targeting dynein to microtubule plus ends, recruiting dynein to membranous cargos and enhancing dynein processivity (the ability to move along a microtubule for a long distance without falling off the track). Can also act as a brake to slow the dynein motor during motility along the microtubule (PubMed:25185702).

Can regulate microtubule stability by promoting microtubule formation, nucleation and polymerization and by inhibiting microtubule catastrophe in neurons. Inhibits microtubule catastrophe by binding both to microtubules and to tubulin, leading to enhanced microtubule stability along the axon (PubMed:23874158).

Plays a role in metaphase spindle orientation (PubMed:22327364).

Plays a role in centriole cohesion and subdistal appendage organization and function. Its recruitment to the centriole in a KIF3A-dependent manner is essential for the maintenance of centriole cohesion and the formation of subdistal appendage. Also required for microtubule anchoring at the mother centriole (PubMed:23386061).

Plays a role in primary cilia formation (PubMed:25774020).

Antigen processing and presentation of exogenous peptide antigen via MHC class II Source: Reactome
Cell division Source: UniProtKB-KW
Centriole-centriole cohesion Source: UniProtKB
Ciliary basal body-plasma membrane docking Source: Reactome
Cytoplasmic microtubule organization Source: GO_Central
Endoplasmic reticulum to Golgi vesicle-mediated transport Source: Reactome
Establishment of mitotic spindle orientation Source: UniProtKB
G2/M transition of mitotic cell cycle Source: Reactome
IRE1-mediated unfolded protein response Source: Reactome
Maintenance of synapse structure Source: ARUK-UCL
Microtubule anchoring at centrosome Source: UniProtKB
Mitotic cell cycle Source: ProtInc
Motor behavior Source: ARUK-UCL
Nervous system development Source: UniProtKB
Neuromuscular junction development Source: ARUK-UCL
Neuromuscular process Source: ARUK-UCL
Neuron cellular homeostasis Source: ARUK-UCL
Neuron projection maintenance Source: ARUK-UCL
Non-motile cilium assembly Source: UniProtKB
Nuclear envelope disassembly Source: UniProtKB
Nuclear migration Source: GO_Central
Positive regulation of microtubule nucleation Source: UniProtKB
Positive regulation of microtubule polymerization Source: UniProtKB
Positive regulation of neuromuscular junction development Source: ARUK-UCL
Regulation of G2/M transition of mitotic cell cycle Source: Reactome
Regulation of mitotic spindle organization Source: UniProtKB
Retrograde transport, endosome to Golgi Source: UniProtKB
Ventral spinal cord development Source: ARUK-UCL

Cytoplasm; Cytoskeleton; Centrosome; Centriole; Spindle; Nucleus envelope; Cell cortex. Localizes to microtubule plus ends (PubMed:17828277, PubMed:22777741, PubMed:25774020). Localizes preferentially to the ends of tyrosinated microtubules (PubMed:26972003). Localization at centrosome is regulated by SLK-dependent phosphorylation (PubMed:23985322). Localizes to centrosome in a PARKDA-dependent manner (PubMed:20719959). Localizes to the subdistal appendage region of the centriole in a KIF3A-dependent manner (PubMed:23386061). PLK1-mediated phosphorylation at Ser-179 is essential for its localization in the nuclear envelope (PubMed:20679239).

Neuronopathy, distal hereditary motor, 7B (HMN7B):
A neuromuscular disorder. Distal hereditary motor neuronopathies constitute a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs.
Amyotrophic lateral sclerosis (ALS):
A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases.
Perry syndrome (PERRYS):
A neuropsychiatric disorder characterized by mental depression not responsive to antidepressant drugs or electroconvulsive therapy, sleep disturbances, exhaustion and marked weight loss. Parkinsonism develops later and respiratory failure occurred terminally.

Ubiquitinated by a SCF complex containing FBXL5, leading to its degradation by the proteasome.
Phosphorylation by SLK at Thr-145, Thr-146 and Thr-147 targets DCTN1 to the centrosome. It is uncertain if SLK phosphorylates all three threonines or one or two of them. PLK1-mediated phosphorylation at Ser-179 is essential for its localization in the nuclear envelope, promotes its dissociation from microtubules during early mitosis and positively regulates nuclear envelope breakdown during prophase.