The Ret finger protein-like (RFPL) protein family members includes RFPL1, RFPL2, RFPL3 and RFPL4. In humans, RFPL transcripts can be detected at the onset of neurogenesis in differentiating human embryonic stem cells, and in the developing human neocortex []. The human RFPL1, 2, 3 genes have a role in neocortex development. RFPL1 is a primate-specific target gene of Pax6, a key transcription factor for pancreas, eye and neocortex development. Human RFPL1, 2 and 3 are reported to impact on cell number, specifically through the RFPL-defining motif (RDM) and SPRY domains []. The RFPL4 (also known as RFPL4A) gene encodes a putative E3 ubiquitin-protein ligase expressed in adult germ cells and interacts with oocyte proteins of the ubiquitin-proteasome degradation pathway [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].This group represents a tyrosine-protein kinase, Ret receptor type.
This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C terminus of Ret finger protein-like (RFPL) protein family, which includes RFPL1, RFPL2, RFPL3 and RFPL4. In humans, RFPL transcripts can be detected at the onset of neurogenesis in differentiating human embryonic stem cells, and in the developing human neocortex []. The human RFPL1, 2, 3 genes have a role in neocortex development. RFPL1 is a primate-specific target gene of Pax6, a key transcription factor for pancreas, eye and neocortex development; human RFPL1 decreases cell number through its RFPL-defining motif (RDM) and SPRY domains []. The RFPL4 (also known as RFPL4A) gene encodes a putative E3 ubiquitin-protein ligase expressed in adult germ cells and interacts with oocyte proteins of the ubiquitin-proteasome degradation pathway [].
The RFPL defining motif (RDM) is a domain found on RFPL (Ret finger protein like) proteins. In humans, RFPL transcripts can be detected at the onset of neurogenesis in differentiating human embryonic stem cells, and in the developing human neocortex []. The RDM domain is thought to have emerged from a neofunctionalisation event. It is found N-terminal to the SPRY domain ().
RET is a single transmembrane-spanning receptor tyrosine kinase (RTK) that plays critical roles in the development of vertebrates. Structural analysis indicate that the ligand-binding RET ectodomain (RET-ECD) contains four consecutive cadherin-like domains (CLD1-CLD4) followed by a membrane-proximal cysteine-rich domain (CRD). This entry relates to CLD4 which is required for CRD folding [].
RET is a single transmembrane-spanning receptor tyrosine kinase (RTK) that plays critical roles in the development of vertebrates. Structural analysis indicate that RET contains four consecutive cadherin-like domains (CLD). This entry relates to CLD3. Classical cadherin calcium-coordinating motifs can be found between CLD2 and CLD3 [].
Ret is a single transmembrane-spanning receptor tyrosine kinase (RTK) that plays critical roles in the development of vertebrates. It contains four consecutive cadherin-like domains (CLD). This entry represents the first CLD at the N-terminal. Several regions within RET-CLD1 have been shown to be important for ligand-coreceptor binding. CLD1 and CLD2 have a distinctive clamshell shape and CLD1 is essential for CLD2 folding. CLD1 contains 2 sites for GDNF receptor alpha 1 binding [].
Proteins in this entry have an N-terminal FKBP-type peptidyl-prolyl cis-trans isomerase domain followed by a C-terminal tetratricopeptide repeat-containing domain. Included in this entry are: aryl-hydrocarbon-interacting protein-like 1 (AIPL1), which is associated with inherited blindness and interacts with cell cycle regulator protein NUB1 []; and AH receptor-interacting protein (AIP), which interacts with the tyrosine kinase receptor RET [], and mutations in AIP are associated with familial isolated pituitary adenomas [].
This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C terminus of TRIM27, also known as RING finger protein 76 (RNF76) or RET finger protein (RFP). TRIM proteins are defined by the presence of the tripartite motif RING/B-box/coiled-coil region and are also known as RBCC proteins []. TRIM27 exhibits either nuclear or cytosolic localization depending on the cell type. TRIM27 negatively regulates nucleotide-binding oligomerizationdomain containing 2 (NOD2)-mediated signaling by proteasomal degradation of NOD2, suggesting that TRIM27 could be a new target for therapeutic intervention in NOD2-associated diseases such as Crohn's []. High expression of TRIM27 is observed in several human cancers, including breast and endometrial cancer, where elevated TRIM27 expression predicts poor prognosis []. Also, TRIM27 forms an oncogenic fusion protein with Ret proto-oncogene. It is involved in different stages of spermatogenesis and its significant expression in male germ cells and seminomas, suggests that TRIM27 may be associated with the regulation of testicular germ cell proliferation and histological-type of germ cell tumors [, ]. TRIM27 could also be a predictive marker for chemoresistance in ovarian cancer patients []. In the neurotoxin model of Parkinson's disease (PD), deficiency of TRIM27 decreases apoptosis and protects dopaminergic neurons, making TRIM27 an effective potential target during the treatment of PD [].
The GDNF family members (consists of GDNF, neurturin, artemin and persephin) are structurally similar to transforming growth factor-beta. Unlike other members of the TGF-beta superfamily, which signal through the receptor serine-threonine kinases, GDNF family ligands activate intracellular signalling cascades via the receptor tyrosine kinase Ret. GDNF family ligands binds to GDNF family receptor alpha (GFRalpha) and then the GDNF family ligand-GFRalpha complex binds to and stimulates autophosphorylation of Ret. For instance, GDNF binds to GFRalpha1, Neurturin binds to GFRalpha2, artemin to GFRalpha3 and persephin activates Ret by binding to GFRalpha4. The GDNF family members support the survival of dopamine neurons and motoneurons, and some of them also regulate the development of enteric, sympathetic and parasympathetic neurons []. GDNF also functions in the regeneration of sensory axons after spinal cord injury [], regulation of spermatogonia renewal and differentiation during male spermatogenesis []. It is also involved in kidney development [].
Glial cell line-derived neurotrophic factor (GDNF) and its related factorsneurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. Homologues for the GFRalpha-1 receptor subtype have been cloned from mammalian and avian tissue. The receptor is activated by GDNF [], although there is evidence it can also bind neurturin, the principal ligand for GFRalpha-2 [].Activation of GFRalpha-1 triggers its interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma) dependent pathways [].
Glial cell line-derived neurotrophic factor (GDNF) and its related factorsneurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. Homologues for the GFRalpha-2 receptor subtype have been cloned from mammalian and avian tissue. The receptor is preferentially activated by neurturin, although there is evidence that GFRalpha-2 can also bindGDNF if pre-coupled to its effector molecule [].Activation of GFRalpha-2 triggers its interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma) dependent pathways [].
Glial cell line-derived neurotrophic factor (GDNF) and its related factorsneurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. GFRalpha-3 has been cloned from mammalian tissue []. It represents the least conserved member of the GFR family in terms of amino acid sequence, and is activated by artemin [].Activation of GFR family members triggers their interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma) dependent pathways [].
Glial cell line-derived neurotrophic factor (GDNF) and its related factorsneurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. GFRalpha-1 and 2 are activated by GDNF and NTN respectively, although some degree of ligand promiscuity is thought to occur []. Homologues for these receptor subtypes have been cloned from mammalian and avian tissue. The principal ligand for GFRalpha-3 is artemin. This receptor subtype is currently described only in mammals []. GFRalpha-4 is activated by persephin and has so far only been found in chicken []. This entry is general for types 1 to 3.Activation of GFR family members triggers their interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma) dependent pathways [].
Glial cell line-derived neurotrophic factor (GDNF) and its related factorsneurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. GFRalpha-1 and 2 are activated by GDNF and NTN respectively, although some degree of ligand promiscuity is thought to occur []. Homologues for these receptor subtypes have been cloned from mammalian and avian tissue. The principal ligand for GFRalpha-3 is artemin. This receptor subtype is currently described only in mammals []. GFRalpha-4 is activated by persephin and has so far only been found in chicken []. This entry is general for types 1 to 3.Activation of GFR family members triggers their interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma)dependent pathways [].
Several proteins that contain RING fingers also contain a well-conserved40-residue cysteine-rich domain termed a B-box zinc finger. Often, one or two copies of the B-box are associated with a coiled coil domain in additionto the ring finger, forming a tripartite motif. The tripartite motif is found in transcription factors, ribonucleoproteins and proto-oncoproteins,but no function has yet been ascribed to the domain [].The solution structure of the B-box motif has been determined by NMR. The protein is a monomer, with 2 β-strands, 2 helical turns and 3extended loop regions packed in a novel topology []. Of 7 potential zincligands, only 4 are used, binding a single zinc atom in a C2-H2 tetrahedral arrangement. The B-box structure differs in tertiary fold from allother known zinc-binding motifs.A group of proteins that contain the B-box motif also host a well conserveddomain of unknown function. Proteins that include this domain are,e.g.: butyrophilin, the RET finger protein, the 52kDa Ro protein and theXenopus nuclear factor protein. The C-terminal portion of this region hasbeen termed the SPRY domain (after SPla and the RYanodine Receptor) [].
