Disease relevance of DOCK1

• We demonstrate that Tyr-56 phosphorylation by DAck diminishes the DSH3PX1 SH3 domain interaction with the Wiskott-Aldrich Syndrome protein while enabling DSH3PX1 to associate with Dock [1].
• Bill Dock and the location of pulmonary tuberculosis: how bed rest might have helped consumption [2].
• The nurses Lavinia Dock and Emma Goldman used the topic of venereal disease as a springboard to discuss their contrasting feminist ideologies [3].

High impact information on DOCK1

• In mammalian cells, ELMO1 functionally cooperates with CrkII and Dock180 to promote phagocytosis and cell shape changes [4].
• C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180 [5].
• Dominant-negative Rac1 suppressed DOCK180-induced membrane spreading [6].
• DOCK180 is involved in integrin signaling through CrkII-p130(Cas) complexes [6].
• Here we report the identification of DOCK7, a member of the DOCK180-related protein superfamily, as a Rac GTPase activator that is asymmetrically distributed in unpolarized hippocampal neurons and selectively expressed in the axon [7].

Biological context of DOCK1

• DOCK180 was originally identified as one of two major proteins bound to the Crk oncogene product and became an archetype of the CDM family of proteins, including Ced-5 of Caenorhabditis elegans and Mbc of Drosophila melanogaster [8].
• Mutagenesis studies reveal that this ELMO PH domain-dependent regulation is essential for the Dock180-ELMO complex to function in phagocytosis and cell migration [9].
• Activation of Rac by laminin-10/11 was associated with the phosphorylation of p130(Cas) and an increased formation of a p130(Cas)-CrkII-DOCK180 complex [10].
• Our studies therefore identify a novel protein domain that interacts with and activates GTPases and suggest the presence of an evolutionarily conserved DOCK180-related superfamily of exchange factors [11].
• Two additional, albeit much weaker, Nck-2 SH3 binding sites are located to DOCK180 residues 1793-1810 and 1835-1852 respectively [12].

Anatomical context of DOCK1

• Whereas wild-type DOCK180 accumulated diffusely in the cytoplasm and did not have any effect on cell morphology, farnesylated DOCK180 was localized on the cytoplasmic membrane and changed spindle 3T3 cells to flat, polygonal cells [13].
• Internalization is dependent upon signalling through the beta5 cytoplasmic tail, and engagement of the alphavbeta5 heterodimer results in recruitment of the p130cas-CrkII-Dock180 molecular complex, which in turn triggers Rac1 activation and phagosome formation [14].
• Interestingly, deletion mutants of ELMO1 missing their first 531 or first 330 amino acids that can still bind and cooperate with Dock180 in Rac activation failed to promote migration, which correlated with the inability to localize to lamellipodia [15].
• DOCK2 mRNA was expressed mostly in peripheral blood cells, followed by slight expression in the spleen and thymus, whereas DOCK180 was expressed in all tissues tested except in peripheral blood cells [16].
• ELMO proteins are also known to regulate actin cytoskeleton reorganization through activation of the small GTPbinding protein Rac via the ELMO-Dock180 complex [17].

Associations of DOCK1 with chemical compounds

• These results suggest that DOCK180 is a new effector molecule which transduces signals from tyrosine kinases through the CRK adaptor protein [13].
• Thus DOCK180 contained a phosphoinositide-binding domain, as did the other guanine nucleotide exchange factors with a Dbl homology domain, and was translocated to the plasma membrane on the activation of PI-3K [8].
• Laminin-10/11 and fibronectin differentially regulate integrin-dependent Rho and Rac activation via p130(Cas)-CrkII-DOCK180 pathway [10].
• Moreover, our data link another PS-dependent signal to the CrkII/Dock180/Rac1 module [18].
• Identification of a DOCK180-related Guanine Nucleotide Exchange Factor That Is Capable of Mediating a Positive Feedback Activation of Cdc42 [19].

Regulatory relationships of DOCK1

• We also found that ELMO1 regulated multiple Dock180 superfamily members to promote migration [15].
• In contrast, membrane ruffling, but not cell contraction, requires Rac GTPase activity and the formation of a CAS/Crk complex that functions in the context of the Rac activating protein DOCK180 [20].
• The ubiquitylation of Dock180 was enhanced by epidermal growth factor (EGF), Crk and adhesion-dependent signals [21].
• Here, the author reports on the characterization of M-DOCK protein, which is closely related to DOCK180 but expressed only in the hematopoietic cells [22].
• Lysyl oxidase regulates actin filament formation through the p130(Cas)/Crk/DOCK180 signaling complex [23].

Other interactions of DOCK1

• DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane [13].
• We have identified in a yeast two-hybrid screen DOCK180, a signaling protein implicated in the regulation of membrane ruffling and migration, as a binding protein for Nck-2 [12].
• Here we show that RhoG interacts directly with Elmo in a GTP-dependent manner and forms a ternary complex with Dock180 to induce activation of Rac1 [24].
• Both cDNAs encoded novel proteins: C3G, a guanine nucleotide exchange protein for Rap1, and DOCK180, an SH3-containing protein of unknown function [25].
• Following the initial landmark finding that Grb2 adapter links the receptors to the Ras pathway leading to DNA synthesis, recent studies have revealed that the biological function of the SH2/SH3 adapter Nck/Dock is to link cell surface receptors to the actin cytoskeleton [26].

Analytical, diagnostic and therapeutic context of DOCK1

• The interaction of the CRK SH3 domain with the DOCK180 peptide was examined with an optical biosensor, based on the principles of surface plasmon resonance [27].
• Surface plasmon resonance analyses reveal that the second and the third SH3 domains interact with the C-terminal region of DOCK180 [12].
• Chromosomal mapping of the gene encoding DOCK180, a major Crk-binding protein, to 10q26.13-q26.3 by fluorescence in situ hybridization [28].

References