Dedicator of cytokinesis protein 2 (Dock2) is a protein encoded in the human by the DOCK2 gene. Dock2 is a large (~180 kDa)
protein involved in
intracellularsignalling networks.[5] It is a member of the DOCK-A subfamily of the
DOCK family of
guanine nucleotide exchange factors (GEFs) which function as activators of
small G-proteins. Dock2 specifically activates isoforms of the small G protein
Rac.
Discovery
Dock2 was first characterised as one of a number of proteins which shared high
sequence similarity with the previously described protein
Dock180, the archetypal member of the DOCK family. Whereas Dock180
expression is near ubiquitous in mammals, Dock2 appears to be expressed specifically in
leukocytes and is considered to be the principal DOCK family member in these cells.[6]
Structure and function
Dock2 is part of a large class of proteins (GEFs) which contribute to cellular signalling events by activating small G proteins. In their resting state G proteins are bound to
Guanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding of
guanosine triphosphate (GTP). GEFs activate G proteins by promoting this nucleotide exchange.
Dock2 and other DOCK family proteins differ from other GEFs in that they do not possess the canonical structure of tandem
DH-
PH domains known to elicit nucleotide exchange. Instead they possess a
DHR2 domain which mediates Rac activation by stabilising it in its nucleotide-free state.[7] They also contain a
DHR1 domain which binds
phospholipids and is required for the interaction between Dock2 and the
plasma membrane.[8] As with other members of the DOCK-A and DOCK-B subfamilies, Dock2 contains an
N-terminalSH3 domain which is involved in binding to
ELMO proteins (see below).[9] Dock180 contains a
C-terminalproline rich region which mediates binding to
Crk, however, Dock2 lacks this feature[6] despite the fact that it is able to bind the Crk-like protein
CrkL.[10]
Regulation of activity
Efficient Dock180 GEF activity in a cellular context is known to require the formation of a
complex between Dock180 and its cognate
adaptor proteins, which assist its translocation to the plasma membrane and binding to Rac.[11][12] Similarly, Dock2 has been shown to form a complex with the well described DOCK-binding protein
ELMO1 and this interaction is required for Dock2-mediated Rac activation in
lymphocyte cell lines.[9] ELMO proteins contain a C-terminal proline-rich region which binds to the N-terminal SH3 domain of DOCK proteins and mediates their recruitment to sites of high Rac availability (primarily the plasma membrane).[12] ELMO proteins also contain a
PH domain which appears to induce
conformational changes in DOCK and thus allow binding to Rac.[13]
^Lu M, Kinchen JM, Rossman KL, et al. (2004). "PH domain of ELMO functions in trans to regulate Rac activation via Dock180". Nature Structural & Molecular Biology. 11 (8): 756–62.
doi:
10.1038/nsmb800.
PMID15247908.
S2CID125990.
^Nishihara H, Maeda M, Tsuda M, et al. (August 2002). "DOCK2 mediates T cell receptor-induced activation of Rac2 and IL-2 transcription". Biochemical and Biophysical Research Communications. 296 (3): 716–20.
doi:
10.1016/S0006-291X(02)00931-2.
PMID12176041.