Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

DOCK2; Dedicator of Cytokinesis 2

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_518

Synonyms

Historical Background

DOCK2 was initially designated by Nishihara et al. in 1999 (Nishihara et al. 1999) as a hematopoietic cell-specific homologue of the CDM (ced-5 of Caenorhabditis elegans, DOCK180 of humans, and myoblast city of Drosophila melanogaster) family proteins. The name “DOCK” was originally designated as “Downstream of CRK” for DOCK180, an archetype of CDM family proteins in 1996 (Hasegawa et al. 1996).

Molecular Mechanism of DOCK2 as a Rac-Specific GEF (Guanine Nucleotide Exchange Factor)

In mammals, 11 DOCK180-related proteins have been identified, and the family members can be subcategorized into four groups denoted DOCK-A, -B, -C, and -D, and DOCK2 belongs to DOCK-A as well as DOCK180 (Fig. 1a) (Cote and Vuori 2007). The structural analysis revealed that DOCK2 consists of an SH3 domain in the N-terminus and DHR (DOCK homology region) -1/2 in the middle to C-terminus (Fig. 1b) (Cote and Vuori 2002). DHR-2 is highly conserved throughout DOCK180-related proteins and identified as a Rac-specific GEF in DOCK2, although DHR-2 in other family proteins, such as DOCK3, may activate Cdc-42. DOCK2 lacks the PXXP motif in the C-terminus which is an indispensable region in DOCK180 for binding to CRK (Hasegawa et al. 1996), while CrkL was identified as a binding partner to DOCK2 through its SH3 domain in the N-terminus (Fig. 2) (Nishihara et al. 2002a). Similar to DOCK180, the interaction of DOCK2 with ELMO1, which was shown to increase the catalytic activity of DOCK180 toward Rac (Lu et al. 2004), was reported (Janardhan et al. 2004; Sanui et al. 2003b).
DOCK2; Dedicator of Cytokinesis 2, Fig. 1

(a) The four subfamilies of human DOCK180-related proteins (DOCK-A, -B, -C, and -D) and the target small GTPases are indicated. DOCK2 belongs to DOCK-A and exclusively activates Rac, but not Cdc42. (b) Schematic diagram of the structure of the human DOCK180 and DOCK2. The DHR-1 domain is a unique evolutionarily conserved domain in all DOCK180-related proteins, and in the case of DOCK180, the DHR-1 domain was revealed to mediate a specific interaction with PtdIns (3, 5)P2 and PtdIns (3, 4, 5)P3 signaling lipids. The DHR-2 domains have been shown to interact with the GTPases of the Rho family including Rac1, 2 and Cdc42 leading to the exchange of GDP for GTP. Inactivation of the DHR-2 domain in DOCK180 has been shown to abrogate Rac activation, cell migration, and phagocytosis, highlighting the significance of this domain in the biological function of the DOCK180-related proteins. DOCK2 lacks the Crk-binding motif in the C-terminus which is an indispensable region in DOCK180 for binding to CRK, while CrkL was identified as a binding partner to DOCK2 through its SH3 domain in the N-terminus

DOCK2; Dedicator of Cytokinesis 2, Fig. 2

The signal transduction through DOCK2. DOCK2 transmits the signals from the several types of the integrins and receptors to small GTPase Rac, and regulates the cell motility, proliferation, and immune reaction of the hematopoietic cells. The protein interaction with CrkL and Elmo has been noted in the regulation of these cellular functions

DOCK2 in Cytoskeletal Regulation and Tumorigenesis

DOCK2 regulates the motility of lymphocytes through actin-cytoskeletal reorganization and also cell proliferation in several types of B lymphocytes through the activation of Rac (Nishihara et al. 2002a; Sanui et al. 2003b; Wang et al. 2010), although DOCK2 itself, and even Rac, seems to lack the oncogenic ability. DOCK2-knockdown of the B-cell lymphoma cell lines using shRNA represented abrogated tumor formation in nude mice, suggesting the prominent role of DOCK2 in the progression of hematopoietic malignancy through DOCK2-Rac-ERK pathway (Wang et al. 2010). In fact, the high-level expression of DOCK2 mRNA in the leukemia/lymphoma cells obtained from the patients’ blood samples has been ascertained (unpublished data).

The Immunomodulatory Role of DOCK2 in Lymphocytes

Because of the exclusive expression of DOCK2 in hematopoietic cells (Nishihara et al. 1999), a hematopoietic cell-specific function such as regulation of immunity had been estimated. The analysis using DOCK2 knockout mice revealed the failure of T- and B-lymphocyte migration toward cytokines in vitro and the lack of their homing into the lymph nodes and the spleen in vivo (Fukui et al. 2001). The activation of DOCK2-Rac pathway is indispensable for CXCL12 (SDF-1)-stimulated human T-lymphocyte adhesion which is mediated by alpha4beta1 integrin (Gollmer et al. 2009), and also CCL21-mediated co-stimulation in CD4 (+) T cells (Garcia-Bernal et al. 2006). In addition, the role of DOCK2 in T-cell receptor (TCR) has been clarified: The in vitro analysis using the dominant negative form of DOCK2 confirmed that DOCK2 mediates TCR-dependent activation of Rac2 leading to the regulation of IL-2 (interleukin-2) promoter activity (Nishihara et al. 2002b), and in DOCK2−/− T cells, antigen-induced translocation of TCR and lipid rafts was significantly impaired, resulting in a marked reduction of antigen-specific T-cell proliferation (Sanui et al. 2003a). Furthermore, DOCK2 seems to be required in T-cell precursors for development into natural killer T cells (Kunisaki et al. 2006b). Taken together, these results indicate that DOCK2 is a key regulator of immunity, and explain the fact that cardiac allografts in DOCK2 knockout mice across a complete mismatch of the major histocompatibility complex molecules were not rejected by preventing potentially alloreactive T cells from recruiting into secondary lymphoid organs (Jiang et al. 2005).

DOCK2 in Myeloid Cell Lineage

Dendritic cells (DCs), macrophages, and neutrophils are also key players in immune response. The equivalent expression of DOCK2 during the maturation from CD34 (+)-myeloid precursor cells to these cells has been observed (unpublished data); therefore, the ubiquitous cellular functions of DOCK2 in this cell lineage are anticipated. In fact, the migration of neutrophil and plasmacytoid DCs was significantly abrogated in DOCK2−/− mice, although myeloid DCs did not show any defects in migration, suggesting the presence of alternative molecules to activate Rac during chemotaxis in myeloid DCs (Gotoh et al. 2008; Kunisaki et al. 2006a). Furthermore, DOCK2 is essential for toll-like receptor (TLR) 7- and 9- mediated interferon-alpha induction in plasmacytoid DCs, which play a key role in antiviral immunity (Gotoh et al. 2010).

Summary

As shown above, DOCK2, i.e., activation of Rac by DOCK2, plays indispensable roles in the regulation of immune response and also in the development of hematopoietic malignancy (Fig. 2). The activation of Rac is modulated by DHR-2, and several effectors for activated Rac have been identified, although the molecular mechanism of the activation of DOCK2 is still unclear. In DOCK180, autoregulation of GEF activity by its SH3 domain, ubiquitylation, and phosphorylation associated with Elmo are regarded, although the details including the upstream molecules remain undefined (Cote and Vuori 2007).

Because deficiency of DOCK2 resulted in impairment of the immune system, pharmacological inhibition of DOCK2 could be beneficial in the treatment for autoimmune diseases (Gotoh et al. 2010) and in preventing graft rejection (Jiang et al. 2005), as well as in the regulation of the progression of hematopoietic malignancy including malignant lymphoma and leukemia (Wang et al. 2010). In addition, DOCK2+ microglia which are associated with human Alzheimer’s disease have been identified in a recent report (Cimino et al. 2009), suggesting that DOCK2 could be a possible therapeutic target for neurodegenerative disorders.

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Graduate School of Medicine, Laboratory of Translational PathologyHokkaido UniversitySapporoJapan