G patch domain-containing protein 3 (GPATCH3) is a transcriptional regulator during embryonic development, activating the CXCR4 promoter. The CXCR4 gene is involved in embryo neural crest cell migration. Because the GPATCH3 protein is detected in human tissues relevant to glaucoma, GPATCH3 may be involved in the pathogenesis of congenital glaucoma []. GPATCH3 is also a negative regulator of retinoic acid-inducible gene I-like receptor-mediated antiviral signaling pathways, a means to control the response triggered by the presence of viral RNA by interacting with VISA (an adaptor of virus-triggered, RLR-mediated induction of innate antiviral responses), and disrupting the assembly of the virus-induced VISA signalosome [].Proteins in this family contain a G-patch domain.
CXCL12 (stromal cell-derived factor-1, SDF1) is a chemokine that regulates development in hematopoietic, cardiovascular and nervous systems, and also regulates diverse cell functions, including differentiation, immune synapse formation, proliferation and survival in the immune system []. CXCL12 has two known receptors, CXCR4 and ACKR3/RDC [, ]. Binding of CXCL12 to CXCR4 induces trimeric G protein signaling leading to activation of the Src, phosphoinositide-3 kinase (PI3K)/AKT, ERK, and JNK pathways, contributing to pro-inflammatory function such as protease production and cellular migration [, ].CXCL12 is constitutively expressed in many tissues. It may also be upregulated in the context of infection and inflammation, acting both as a homeostatic and inflammatory chemokine [].
This entry contains proteins with a CCCH-type zinc finger, which bind zinc via cysteine and histidine residues in the motif C-x8-C-x5-C-x3-H, and a C3HC4 type RING finger. Proteins with this structure include:Pre-mRNA-splicing factor CWC24, a component of the CWC complex, which is involved in pre-mRNA splicing [].RING finger protein 113A, an E3 ubiquitin-protein ligase that catalyzes polyubiquitination of SNRNP200/BRR2 with non-canonical 'Lys-63'-linked polyubiquitin chains []and CXCR4, leading to its degradation and thereby termination of CXCR4 signaling [].RING finger protein 113B, which is uncharacterized.
CXC chemokine receptor 4 (CXCR4), also known as fusin, which is a specific receptor for a CXCL12 (or SDF1). CXCR4 has a wide cellular distribution, with expression on most immature and mature hematopoietic cell types [, , , , ]. In addition, CXCR4 can also be found on vascular endothelial cells and neuronal/nerve cells []. Upon binding to CXCR4, CXCL12 causes mobilisation of intracellular calcium and chemotaxis [, , ]. CXCL12 is known to be important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. CXCR4 has a rather broad activity, and has been linked to cardiac, cerebellar gastric vasculature development [, ]and to hematopoiesis []. Atypical chemokine receptor 2 (ACKR2/D6) []is a chemokine-scavenging receptor or chemokine decoy receptor. It is capable of internalising and effectively scavenging its ligands through beta-arrestin-dependent activation of the cofilin pathway [, ]. ACKR2 is highly promiscuous and can bin the majority of (if not all) inflammatory CC-chemokines []. It plays an essential role in the resolution of the inflammatory response [, , ]. Although it lacks the canonical DRYLAIV motif necessary for classical signalling, ACKR2/D6 may be involved in 'atypical' signaling pathways downstream of ligand binding []. It has been shown to be involved in regulating vessel density [].
Synaptotagmin-3 (SYT3) belongs to the synaptotagmin family, which is a group of membrane-trafficking proteins that contain two C-terminal C2 domains. Most of the synaptotagmins have a unique N-terminal domain that is involved in membrane anchoring or specific ligand binding. SYT3 is required for the formation and delivery of cargo to the perinuclear endocytic recycling compartment (ERC) []. Among synaptotagmins 1-11, SYT3 is the only one that is expressed in T cells. It is essential for chemokine receptor CXCR4 recycling in T cells and thereby affects CXCL12 chemokine-induced migration [].
Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role []. They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system [], and endothelial cells, where they may act as either angiogenic or angiostatic factors [].The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors []. Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells [, ]. Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).The CXC chemokine receptors are a subfamily of chemokine receptors that specifically bind and respond to cytokines of the CXC chemokine family. There are currently seven known CXC chemokine receptors in mammals, CXCR1 through to CXCR7.This entry represents the N-terminal region of the CXC type 4 chemokine receptor. CXCR4 and its ligand stromal cell-derived factor-1 (also known as CXCL12) are essential for proper fetal development. CXCR4 is also the major coreceptor for T-tropicstrains of Human immunodeficiency virus 1, and SDF-1 inhibits HIV-1 infection. Additionally, SDF-1 and CXCR4 mediate cancer cell migration and metastasis. The N-terminal domain of most chemokine receptors is the ligand binding domain and so the N-terminal domain of CXCR4 is the binding site for SDF-1 [].
DTX3L is a RING-domain E3 ubiquitin-protein ligase that regulates endosomal sorting of the G protein-coupled receptor CXCR4 from endosomes to lysosomes []. It also regulates subcellular localization of its partner protein, B aggressive lymphoma (BAL), by a dynamic nucleocytoplasmic trafficking mechanism [, }. DTX3L has a unique N terminus, but lacks the highly basic N-terminal motif and the central proline-rich motif present in other Deltex (DTX) family members, such as DTX1, DTX2, and DTX4. Moreover, its C-terminal region is highly homologous to DTX3. It includes a C3HC4-type RING-HC finger, and a previously unidentified C-terminal domain. DTX3L can associate with DTX1 through its unique N terminus and further enhance self-ubiquitination [].
PTKs catalyse the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Itk, also known as Tsk or Emt, is a member of the Tec-like subfamily of proteins, which are cytoplasmic (or nonreceptor) PTKs with similarity to Src kinases in that they contain Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Unlike Src kinases, most Tec subfamily members except Rlk also contain an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation. In addition, Itk contains the Tec homology (TH) domain containing one proline-rich region and a zinc-binding region [, ].Itk is expressed in T-cells and mast cells, and is important in their development and differentiation []. Of the three Tec kinases expressed in T-cells, Itk plays the predominant role in T-cell receptor (TCR) signalling. It is activated by phosphorylation upon TCR crosslinking and is involved in the pathway resulting in phospholipase C-gamma1 activation and actin polymerization []. It also plays a role in the downstream signalling of the T-cell costimulatory receptor CD28, the T-cell surface receptor CD2, and the chemokine receptor CXCR4 [, ]. In addition, Itk is crucial for the development of T-helper(Th)2 effector responses [].
ITK (also known as Tsk or Emt) is a member of the Tec family, which is a group of nonreceptor tyrosine kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation [], and the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions. ITK is expressed in T-cells and mast cells, and is important in their development and differentiation [, ]. Of the three Tec kinases expressed in T-cells, ITK plays the predominant role in T-cell receptor (TCR) signaling. It is activated by phosphorylation upon TCR crosslinking and is involved in the pathway resulting in phospholipase C-gamma1 activation and actin polymerization []. It also plays a role in the downstream signaling of the T-cell costimulatory receptor CD28 [], the T-cell surface receptor CD2 [], and the chemokine receptor CXCR4 []. In addition, ITK is crucial for the development of T-helper(Th)2 effector responses []. This entry represents the SH3 domain of ITK.
