Disease relevance of DOCK2

• DOCK2-deficient mice (DOCK2-/-) exhibited migration defects of T and B lymphocytes, but not of monocytes, in response to chemokines, resulting in several abnormalities including T lymphocytopenia, atrophy of lymphoid follicles and loss of marginal-zone B cells [1].
• On the other hand, we found that the expression of ELMO1 induces Rac activation in the plasmacytoma cells expressing DOCK2 but not ELMO1 [2].

High impact information on DOCK2

• Thus, in lymphocyte migration DOCK2 functions as a central regulator that mediates cytoskeletal reorganization through Rac activation [1].
• Here, we review the role of DOCK2 in lymphocyte homing to lymphoid tissues and discuss recent findings for other CDM family molecules that provide a basis for understanding how DOCK2 might function in lymphocytes [3].
• In summary, our data support a central role for DOCK2, and to a lesser extent T cell-expressed PI3Kgamma, for signal transduction during interstitial lymphocyte migration and S1P-mediated egress [4].
• These findings correlated with delayed lymphocyte egress from PLNs in the absence of DOCK2 but not PI3Kgamma, and a markedly reduced cell motility of DOCK2-deficient T cells in close proximity to efferent lymphatic vessels [4].
• A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate-mediated egress [4].

Biological context of DOCK2

• In this study, we demonstrated that DOCK2 bound to CrkL, which is present exclusively in hematopoietic cells both in vivo and in vitro, and we also found that 2 separate regions of DOCK2 contributed to its binding to Src homology 3 (SH3) domain of CrkL [5].
• Here we show that DOCK2, a haematopoietic cell-specific CDM family protein, is indispensable for lymphocyte chemotaxis [1].

Anatomical context of DOCK2

• DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines [5].
• Colocalization of DOCK2 with Crk-like (CrkL) and F-actin was shown by immunocytochemical analysis with the use of Jurkat cells [5].
• Immunostaining of human cadaver tissues revealed that the expression of DOCK2 was limited to the lymphocytes and macrophages of various organs [6].
• 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 [6].
• DOCK2 plays a critical role in lymphocyte migration by regulating actin cytoskeleton through Rac activation, yet the mechanism by which DOCK2 activates Rac remains unknown [2].

Associations of DOCK2 with chemical compounds

• DOCK2 is Required for Chemokine-Promoted Human T Lymphocyte Adhesion Under Shear Stress Mediated by the Integrin {alpha}4beta1 [7].
• In this study, we investigated the role of DOCK2, a lymphocyte guanine-nucleotide exchange factor also involved in Rac activation, in CXCL12-stimulated human T lymphocyte adhesion mediated by alpha(4)beta(1) [7].

Regulatory relationships of DOCK2

• DOCK2 regulates Rac activation and cytoskeletal reorganization through interaction with ELMO1 [2].
• DOCK2 regulates chemokine-triggered lateral lymphocyte motility but not transendothelial migration [8].

Other interactions of DOCK2

• In addition, the stable expression of DOCK2 in Jurkat cells exhibited the elevated activity of endogenous Rac2 [9].
• We found that DOCK2 associates with engulfment and cell motility (ELMO1) through its Src-homology 3 (SH3) domain [2].
• We have further provided evidence that the DOCK4-Ex49 binds to nucleotide free Rac as effectively as DOCK2 and DOCK4 and it is a potent Rac activator [10].
• The present studies addressed the role of DOCK2 in chemokine-triggered lymphocyte adhesion and motility [8].
• Strikingly, arrested DOCK2(-/-) lymphocytes transmigrated through a CCL21-presenting endothelial barrier with similar efficiency and rate as wt lymphocytes but, unlike wt lymphocytes, could not locomote away from the transmigration site of the basal endothelial side [8].

References