8.A.23 The Basigin (Basigin) Family
Basigin precursor protein of humans is also called CD147, 5F7, emmprin, leukocyte activation antigen, MP, (tumor-derived) collagenase stimulating factor, and extracellular matrix metalloproteinase inhibitor. It is a chaperone glycoprotein with an N-terminal leader peptide that is probably removed by proteolysis after secretion. It has a second TMS near its C-terminus. Additionally, it has two IGcan immunoglobulin-like cell adhesion domains (positions 20-110 and 220-310). The protein directs transporters such as MCT1, MCT2. MCT3 amd MCT4 but not MCT8 (2.A.1.13) to the plasma membrane and remains bound to them, being required for activity and for sensitivity to inhibition by organomercurials (Wilson et al., 2005; Halestrap 2013). It appears to regulate complex I activity and apoptosis in mitochondria by interacting with mitochondrial NDUFS6 (Luo et al. 2014). It has many homologues in vertebrate and invertebrate animals, and several of these have been functionaly characterized. The role of basigin in regulating many transporters has been reviewed (Muramatsu 2016). The basigin Ig-I domain mediates interactions with monocarboxylate transporters (MCTs, TC# 2.A.1.13) which are required for the transporter to reach the plasma membrane during biogenesis and also affects the activities of these transporters (Köpnick et al. 2021). Plasmodium yoelii erythrocyte binding like protein interacts with basigin, an erythrocyte surface protein (Yuguchi et al. 2021).
Basigin is the receptor for cyclophilins, S100A9, and platelet GPVI, while basigin-1 serves as the receptor for the rod-derived cone viability factor (Muramatsu 2015). As noted above, basigin tightly associates with monocarboxylate transporters, and is essential for their cell surface translocation and activities, but it also associates with other proteins including GLUT1, CD44, and CD98. The carbohydrate portion is recognized by lectins, such as galectin-3 and E-selectin. These molecular recognitions form the basis for the role of basigin in the transport of nutrients, migration of inflammatory leukocytes, and induction of matrix metalloproteinases. Basigin is important in vision, spermatogenesis, and other physiological phenomena, and plays roles in the pathogenesis of numerous diseases, including cancer. It is also the receptor for an invasive protein RH5, which is present in malaria parasites. Loss of Basigin expression in uterine cells leads to subfertility in female mice (Li et al. 2021).
Contactin 2, a glycosylphosphatidylinositol-anchored neuronal membrane protein, and another transmembrane protein called contactin associated protein-like 2 (CNTNAP2 alias CASPR2) are together necessary to maintain voltage-gated potassium channels at the juxtaparanodal region. CNTN2 knockout mice were previously reported to suffer from spontaneous seizures and mutations in the CNTNAP2 gene have been described to cause myoclonic tremor and epilepsy in humans (Stogmann et al. 2013).
The rat liver C-BAT is a 110 kDa glycoprotein (GP110) of 519 amino acids. Its short C-terminus is in the cytoplasm, it spans the membrane once, and the majority of the protein is external. It contains the ATP-binding consensus site (residues 92-100) of GPAYSGRET and is an ecto-ATPase. Transfection of heterologous cells with the cDNA encoding this protein conferred both bile acid transport and ecto-ATPase activity to the recipient cells (Sippel et al. 1993; 1994). Taurocholate is pumped out of the cell. Transport (but not ATPase activity) appears to be stimulated by protein kinase C-mediated phosphorylation of the C-terminal domain. The ecto-ATPase activity of this protein does not appear to mediate transport although reduction in the cytoplasmic ATP concentration reduces the transport rate. Both ATP and the membrane potential have been implicated as energy sources for transport.
The topology of the rat liver C-BAT protein as a Type I membrane protein, the dissection of its transport activity from its ecto-ATPase activity, its homology to members of the carcinogenic antigen superfamily and its identification as a calcium-independent cell adhesin in the apical membrane of the hepatocyte all suggest that this protein does not alone function as a bile acid efflux pump (Suchy et al. 1997). The involvement of at least one other protein is suggested, and this other protein may be the primary bile acid export permease. GP110 may thus be an accessory protein, possibly an activator that is responsive to protein kinase (Halestrap 2013).
Neuroplastins are homologous to and function like basigins. Of these, both np65 and np55 induce neurite outgrowth, and both activate the FGF receptor and associated downstream signalling pathways. Np65 binds to and colocalises with GABA(A) receptor subtypes (TC # 1.A.9) and may play a role in anchoring them to specific synaptic and extrasynaptic sites. The neuroplastins have been shown to chaperone and support the monocarboxylate transporter MCT2 in transporting lactate across the neuronal plasma membrane. The neuroplastins are multifunctional adhesins that support neurite outgrowth, modulate long-term activity-dependent synaptic plasticity, regulate surface expression of GluR1 receptors, modulate GABA(A) receptor localisation, and play a key role in delivery of monocarboxylate energy substrates both to the synapse and to extrasynaptic sites (Beesley et al. 2014).
Viral entry into the host cell is the first step towards successful infection. Viral entry starts with virion attachment, and binding to receptors. Receptor binding viruses either directly release their genomes into the cell, or enter cells through endocytosis. For DNA viruses and a few RNA viruses, the endocytosed viruses is transported from cytoplasm into the nucleus followed by gene expression. The receptor for infection by white spot syndrome virus (WSSV) for kuruma shrimp, Marsupenaeus japonicus, is a member of the immunoglobulin superfamily (IgSF) with a transmembrane region, and is similar to the vertebrate polymeric immunoglobulin receptor (pIgR). MjpIgR was detected in all tissues tested, and its expression was induced by WSSV infection. Knockdown of MjpIgR, and blocking MjpIgR with its antibody inhibited WSSV infection, and overexpression facilitated the invasion. The extracellular domain of MjpIgR interacts with envelope protein VP24 of WSSV and the intracellular domain interacts with calmodulin (MjCaM). MjpIgR oligomerizes and is internalized by clathrin-dependent endocytosis (Niu et al. 2019).
CD4 is an integral membrane glycoprotein that plays an essential role in the immune response and serves multiple functions in responses to both external and internal stimuli. In T-cells, it functions primarily as a coreceptor for MHC class II molecule:peptide complex (Doyle and Strominger 2006). The antigens presented by class II peptides are derived from extracellular proteins while class I peptides are derived from cytosolic proteins. CD4 interacts simultaneously with the T-cell receptor (TCR) and the MHC class II presented by antigen-presenting cells (APCs) (Bernstein et al. 2006). In turn, it recruits the Src kinase LCK to the vicinity of the TCR-CD3 complex. LCK then initiates different intracellular signaling pathways by phosphorylating various substrates, ultimately leading to lymphokine production, motility, adhesion and activation of T-helper cells. In other cells such as macrophages or NK cells, it plays a role in differentiation/activation, cytokine expression and cell migration in a TCR/LCK-independent pathway (Zhen et al. 2014) while participating in the development of T-helper cells in the thymus and triggering the differentiation of monocytes into functional mature macrophages (Zhen et al. 2014). It is the primary receptor for human immunodeficiency virus-1 (HIV-1) (Crise et al. 1990, Sharma et al. 2005, Matthias et al. 2002). It is down-regulated by HIV-1 Vpu (Lindwasser et al. 2007) and acts as a receptor for human Herpes virus 7/HHV-7 (Lusso et al. 1994). CD4 and its co-receptor, CCR5, exist in the membrane in a fluid state that may be essential for membrane fusion between the viral envelop and the cell membrane (Matthias et al. 2002).
Ephrin-B1 is one of the critical components of the slit diaphragm of kidney glomerular podocytes. Ephrin-B1-associated molecules were studied (Fukusumi et al. 2021). Na+/H+ exchanger regulatory factor 2 (NHERF2), a scaffolding protein, is associated with ephrin-B1. NHERF2 was expressed in the apical area and the slit diaphragm, and it interacted with the nephrin-ephrin-B1 complex at the slit diaphragm. The nephrin-ephrin-B1-NHERF2 complex interacted with ezrin bound to F-actin. NHERF2 bound ephrin-B1 via its first postsynaptic density protein-95/disks large/zonula occludens-1 domain, and podocalyxin via its second postsynaptic density protein-95/disks large/zonula occludens-1 domain. Phosphorylation of nephrin and ephrin-B1, and dephosphorylation of NHERF2 and ezrin, disrupted the linkages of ephrin-B1-NHERF2 and NHERF2-ezrin (Fukusumi et al. 2021).
Interactions between the polysialylated neural cell adhesion molecule (TC# 8.A.23.1.49) and the transient receptor potential canonical channels TrpC1, 4, and 5 induce entry of Ca2+ into neurons (Amores-Bonet et al. 2022). NCAMs play roles in the developing and mature nervous systems. Amores-Bonet et al. 2022 showed that the transient receptor potential canonical (TRPC) ion channels TRPC1, -4, and -5 not only interact with the intracellular domains of the transmembrane isoforms NCAM140 and NCAM180, but also with the glycan polysialic acid (PSA) covalently attached to the NCAM protein backbone. NCAM antibody treatment leads to the opening of TRPC1, -4, and -5 hetero- or homomers at the plasma membrane and to the influx of Ca2+ into cultured cortical neurons and CHO cells expressing NCAM, PSA, and TRPC1 and -4 or TRPC1 and -5. NCAM-stimulated Ca2+ entry was blocked by the TRPC inhibitor Pico145 or the bacterial PSA homolog colominic acid. NCAM-stimulated Ca2+ influx was detectable neither in NCAM-deficient cortical neurons nor in TRPC1/4- or TRPC1/5-expressing CHO cells that express NCAM, but not PSA. NCAM-induced neurite outgrowth was reduced by TRPC inhibitors and a function-blocking TRPC1 antibody. A characteristic signaling feature was that extracellular signal-regulated kinase 1/2 phosphorylation was also reduced by TRPC inhibitors. This indicates that the interaction of NCAM with TRPC1, -4, and -5 contributes to the NCAM-stimulated and PSA-dependent Ca2+ entry into neurons, thereby influencing essential neural functions (Amores-Bonet et al. 2022).
References:
Extracellular chaperone protein precursor, Basigin (BSG; CD147). It interacts with MCT1, 3 and 4 (TC# 2.A.1.13.1, 7 and 9, respectively) (Ovens et al., 2010; Halestrap 2012). May play a role in cancer progression (Kendrick et al. 2016). Silencing of CD147 inhibits hepatic stellate cell activation related to suppressing aerobic glycolysis via hedgehog signaling (Li et al. 2021).
Animals
Basigin precursor of Homo sapiens (P35613)
Activated leukocyte cell adhesion molecule, ALCAM or CD166 antigen, of 583 aas and 2 TMSs, N- and C-terminal. It is expressed on and in the cell membranes of various cells. In the spinal cord dorsal horn (DH), the first gate for the sensory and pain transmission to the brain, ALCAM plays modulatory roles in the excitatory synaptic transmission and plasticity in the (rat) spinal DH (Park et al. 2017).
ALCAM of Homo sapiens
Interleukin 1 receptor of 569 aas and 2 TMSs, N-terminal and near the middle of the protein. It is the receptor for IL1A, IL1B and IL1RN. After binding to interleukin-1, it associates with the coreceptor IL1RAP to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependent activation of NF-kappa-B, MAPK and other pathways. Signaling involves the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAK1 or IRAK2 via the respective TIR domains of the receptor/coreceptor subunits. It binds ligands with comparable affinity, and binding of antagonist IL1RN prevents association with IL1RAP to form a signaling complex (Slack et al. 2000).
IL-1R of Homo sapiens
cSrc tyr kinase of 536 aas; regulates the Na+,K+-ATPase and connexin 43, probably by direct phosphorylation (Giepmans 2006).
cSrc of Homo sapiens
Epidermal growth factor receptor (EGFR) of 1426 aas and 2 or more TMSs. Binds to four ligands: Spitz, Gurken, Vein and Argos, transducing signals through the ras-raf-MAPK pathway. Involved in a myriad of developmental decisions (Geiger et al. 2011).
EGFR of Drosophila melanogaster (Fruit fly)
Coxsackievirus and adenovirus receptor, CAR, of 365 aas and 2 TMSs near the N- and C-termini. It is a component of the epithelial apical junction complex that may function as a homophilic cell adhesion molecule and is essential for tight junction integrity. It is also involved in transepithelial migration of leukocytes through adhesive interactions with JAML, a transmembrane protein of the plasma membrane of leukocytes (Cohen et al. 2001). It's subcellular distribution has been studied (Ifie et al. 2018). The CAR in zebrafish (Q90Y50) has been discussed (Rathjen 2020).
CAR of Homo sapiens
Ephrin type-B receptor 4 (EPHB4; EC:2.7.10.1). Alternative name(s): Hepatoma transmembrane kinase; Tyrosine-protein kinase, TYRO11. It is a receptor tyrosine kinase which binds
promiscuously transmembrane ephrin-B family ligands residing on adjacent
cells, leading to contact-dependent bidirectional signaling into
neighboring cells. It plays a role in postnatal blood vessel remodeling, morphogenesis and permeability (Erber et al. 2006; Martin-Almedina et al. 2016).
EPHB4 of Homo sapiens
Angiopoietin-1 receptor of 1072 aas, Tek, a tyrosyl protein kinase (Ward and Dumont 2002).
Animals
Tek of Mus musculus
Receptor tyrosyl protein kinase, ErbB4 (ErbB-4). Plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis (Deng et al. 2013).
ErbB4 of Homo sapiens
Tex14 of 1497 aas and 1 or 2 TMSs. Required both for the formation of
intercellular bridges during meiosis and for kinetochore-microtubule
attachment during mitosis. Intercellular bridges, called 'ring canals', probably result from nurse cell fusion with the developing oocyte. They are evolutionarily
conserved structures that connect differentiating germ cells and are
required for spermatogenesis, oogenesis and male fertility. They act by promoting the
conversion of midbodies into intercellular bridges via its interaction
with CEP55. Interaction with CEP55 inhibits the interaction between
CEP55 and PDCD6IP/ALIX and TSG101, blocking cell abscission and leading
to transformation of midbodies into intercellular bridges. In spite of its PK domain, it has no protein kinase activity in vitro (Lei and Spradling 2016).
Tex14 of Homo sapiens
The Advanced glycosylation end product-specific receptor of 404 aas and 2 TMSs, N- and C-terminal, AGER or RAGE. It is the receptor for amyloid beta peptide, and it contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons. ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space. RAGE also has a number of other functions (Fang et al. 2010;.Jin et al. 2011). It's structure is known to 1.5 Å resolution (Park et al. 2010; Xue et al. 2011).
;
RAGE of Homo sapiens
Extracellular chaperone protein precursor, Embigin. Interacts with MCT2 (2.A.1.13.5) (Ovens et al., 2010; Halestrap 2012). Embigin facilitates monocarboxylate transporter 1 localization to the plasma membrane and its transition to a decoupling state (Xu et al. 2022).
Animals
Embigin of Homo sapiens (Q6PCB8)
Polymeric immunoglobulin receptor-like protein, pIgR, of 562 aas and 2 TMSs, one N-terminal and one near the C-terminus of the protein. It is the receptor for white spot syndrome virus (WSSV) infection (Niu et al. 2019).
pIgR of Penaeus japonicus (Kuruma prawn) (Marsupenaeus japonicus)
Polymeric Ig-like receptor of 345 aas and 2 TMSs, pIgR, also called Cell adhesion molecule 4 isoform X2.
pIgR of Homo sapiens
Polymeric Ig-like receptor family protein, pIgR, of 774 aas and 1 TMS, near the C-terminus.
pIgR of Drosophila melanogaster (Fruit fly)
Poliovirus receptor-related protein 3-like isoform X, PVRL3, of 366 aas and 1 N-terminal TMS
PVRL3 of Lipotes vexillifer (Yangtze river dolphin)
Uncharacterized protein of 323 aas and 2 TMSs, N- and C-terminal.
UP of Strongylocentrotus purpuratus
T-cell surface antigen CD2 of 351 aas. CD2 interacts with lymphocyte function-associated antigen CD58 (LFA-3) and CD48/BCM1 to mediate adhesion between T-cells and other cell types. CD2 is implicated in the triggering of T-cells, and the cytoplasmic domain is implicated in the signaling function.
CD2 of Homo sapiens
Carcinoembryonic antigen-related cell adhesion molecule 1-like protein of 663 aas and 1 TMS. This protein appears to be related to members of family 8.A.128, and these two families may comprise a superfamily.
Adhesin of Xenopus laevis
TGF-β (Tkv) receptor protein kinase of 575 aas and 1 TMS (Bartoszewski et al. 2004).
Tkv receptor of Drosophila melanogaster (Fruit fly)
Neural cell adhesion molecule 2-like protein of 567 aas and 2 TMSs, N- and C-terminal.
Adhesion protein of Astatotilapia calliptera (eastern happy)
Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle (Tan-Sindhunata et al. 2015). Recruitment of AGRIN by LRP4 to the MUSK signaling complex induces phosphorylation and activation of MUSK, the kinase of the complex (Koppel et al. 2019).
MUSK of Homo sapiens
Potassium channel associated protein, contactin 2, CNTN2, of 1040 aas and possibly 2 TMSs, at the N- and C-termini. Mutations are associated with autosomal recessive cortical myoclonic tremors and epilepsy (Stogmann et al. 2013).
Animals
CNTN2 of Homo sapiens
Insulin receptor-like tyrosine kinase, DAF2, of 1846 aas and 3 putative TMSs, one near the N-terminus, and two in the C-terminal part ofthe protein. It regulates metabolism, controls longevity and prevents developmental arrest at the dauer stage (Fierro-González et al. 2011; Tiku et al. 2017; Chen et al. 2013). The nematode insulin receptor (IR), DAF-2B, modulates insulin signaling by sequestration of insulin peptides (Martinez et al. 2020).
DAF2 of Caenorhabditis elegans
Hemicentin-1-like protein of 321 aas and 0 - 4 TMSs.
Him1 of Penaeus vannamei
Self-ligand receptor of the signaling lymphocytic activation molecule (SLAM) family-6, SlamF6, of 351 aas and possibly 3 TMSs, two near the N-terminus, and one near the C-terminus (Togni et al. 2004). SLAM receptors, triggered by homo- or heterotypic cell-cell interactions, modulate the activation and differentiation of a wide variety of immune cells and thus are involved in the regulation and interconnection of both innate and adaptive immune responses (Griewank et al. 2007).
SlamF6 of Mus musculus (Mouse)
Nephrin, NPHS1 of 1241 aas and two TMSs, one at the N-terminus, and one near the C-terminus of the protein. Nephrin forms a complex with podocin (TC# 3.A.16.1.1), CD2AP (8.A.34.1.5) and TRPC6 (1.A.4.1.5) to form a macromolecular assembly that constitutes the slit-diaphragm in podocytes, a tight juntion-like complex (Mulukala et al. 2020).
Nephin of Homo sapiens
Signal-regulatory protein beta-1, SIRPbeta (SIRPβ) of 398 aas and 2 TMSs, N- and C-terminal. It is an immunoglobulin-like cell surface receptor involved in the negative regulation of receptor tyrosine kinase-coupled signaling processes, and it participates in the recruitment of tyrosine kinase SYK. It triggers activation of myeloid cells when associated with TYROBP (Dietrich et al. 2000). Positive regulation of phagocytosis by SIRPbeta has been demonstrated as part of its signaling mechanism in macrophages (Hayashi et al. 2004).
SIRPβ of Homo sapiens
Serine/threonine-protein kinase LMTK1 (AATK) of 1374 aas and one N-terminal TMS. It plays a role in axon outgrowth and spine formation (Wei et al. 2020).
LMTK1 of Homo sapiens
CD48 antigen (BCM1; BLAST1; Sgp-60; MEM102; SLAM family member 2, SLAMF2) of 243 aas with 2 TMSs, N- and C-terminal. It is a ligand for CD2, and may facilitate interaction between activated lymphocytes. It is probably involved in regulating T-cell activation (González-Cabrero et al. 1999).
BCM1 of Homo sapiens
Platelet-derived growth factor receptor beta, PDGFRB, a tyrosine-protein kinase that acts as a cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB (Kelly et al. 1991), and plays an essential role in the regulation of embryonic development, cell proliferation, survival, Ca2+ transport, differentiation, chemotaxis and migration (Kazlauskas et al. 1991; Vanlandewijck et al. 2015). It has been associated with Primary Familial Brain Calcification (PFBC) (Monfrini et al. 2023).
PDGFRB of Homo sapiens
BDNF/NT-3 growth factors receptor, ofNKRK2 or TrkB, of 822 aas and 1 N-terminal TMS. It is a receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity. It is a receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin-4. Alternatively, it can bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2 (Haniu et al. 1995, Yeo et al. 2004). Upon ligand-binding, it undergoes homodimerization, autophosphorylation and activation (Yeo et al. 2004).
TrkB of Homo sapiens
Receptor tyrosine-protein kinase ErbB-2/ErbB-3. ErbB-2 is also called ERBB2, HER2, MLN19, NEU and NGL. It is of 1255 aas and possibly 2 TMSs, one at the N-terminus, and one large hydrophobic peak in the C-terminal half of the protein. ErbB-3 is also called HER3 and is of 1342 aas with at least one TMS near residue 650, but maybe also an N-terminal TMS. These two proteins form a complex with SorLA (TC# 9.B.87.1.17) (Al-Akhrass et al. 2021). They are parts of several cell surface receptor
complexes that apparently need a coreceptor for ligand binding. They are essential components of a neuregulin-receptor complex (Ieguchi et al. 2010).
HER2/HER3 of Homo sapiens
Bone morphogenetic protein receptor type-1B, BMPR-1B or FecB, of 502 aas and one large peak of hydrophobicity at ~residue 140, as well as four smaller peaks of hydrophobicity nearer the C-terminus of the protein that could be TMSs (Lv et al. 2022).
fecB of Ovis aries (sheep)
Macrophage colony-stimulating factor 1 receptor, CSF1R or FMS of 972 aas and 2 or 3 TMSs, one at the N-terminus, one large peak of hydrophobicity at ~ residue 520, and a much smaller peak at residue 650. It is a tyrosine-protein kinase that acts as a cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. It promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. It regulates bone resorption and is required for normal bone and tooth development. It is also required for normal male and female fertility, and for normal development of milk ducts. It promotes cancer cell invasion and activates several signaling pathways in response to ligand binding, including the ERK1/2 and the JNK pathways (Wei et al. 2010, Guo et al. 2019). High expression of CSF-1R predicts poor prognosis in colon adenocarcinoma (Wang et al. 2022).
CSF1R of Homo sapiens
Dual leucine zipper kinase, Dlk, or mitogen-activated protein kinase kinase kinase 12, MAP3K12, of 859 aas and possibly two adjacent TMSs. It is part of a non-canonical MAPK signaling pathway (Huang et al. 2017).
DLK of Homo sapiens
Vascular endothelial growth factor receptor 3,VGFR3, of 1363 aas and 2 TMSs, N-terminal and at residue 780.
VGFR3 of Homo sapiens
Proto-oncogene tyrosine-protein kinase receptor, Ret, of 1114 aas and 2 TMSs. N-terminal and at residue 645. The cryoEM structure is available (Cai et al. 2022).
RET of Homo sapiens
Hepatocyte growth factor receptor, Met, of 1390 aas and 2 TMSs, one N-terminal and one at residue 945. A cryoEM strucure is available (Cai et al. 2022).
MET of Homo sapiens
Epidermal growth factor receptor, EGFR, of 1210 aas and two TMSs, one N-terminal and one at residue 655. The CryoEM 3-d structure is available (Cai et al. 2022).
EGFR of Homo sapiens
Receptor tyrosine-protein kinase ErbB-2 or HERS of 1255 aas and one TMS at residue 350. A 3-d cryoEM structure is available (Cai et al. 2022).
EbrB-2 of Homo sapiens
Serine, threonine protein kinase B, BraF, of 766 aas and probably 0 TMSs. In thyroid cancer, BRAF V600E regulates the mitochondrial permeability transition through the pERK-pGSK-CypD pathway to resist death, providing intervention targets for BRAF V600E mutant tumours (Gao et al. 2022). Co-dependent regulation of p-BRAF and potassium channel KCNMA1 (TC# 1.A.1.3.10) levels drives glioma progression (Xie et al. 2023).
BraF of Homo sapiens
Neural cell adhesion molecule, NCAM, of 858 aas. This glycoprotein interacts with TrpC1, C4 and C5 to enhance their Ca2+ transport activities (Amores-Bonet et al. 2022)
NCAM proteins of Homo sapiens
Hepatocyte cell adhesion molecule (CAM) precursor of 416 aas. Important for interactions, trafficking and function of ClC2 (CLC-2) in several tissues including the nervious system where it influences human leukodystrophies (Capdevila-Nortes et al. 2015).
Animals
CAM of Homo sapiens
Ser/Thr protein kinase, WNK4, of 1243 aas and possibly 2 TMSs. Plays a role in the regulation of electrolyte homeostasis, cell signaling, survival and proliferation. It acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters, respectively (Hoorn and de Baaij 2022).
WNK4 of Homo sapiens
General control nonderepressible kinase 2 of 1699 aas and 0-2 TMSs. Also called eukaryotic translation initiation factor 2-alpha kinase, Gcn-2. Serine/threonine-protein kinase which phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (eIF2alpha), leading to its inactivation and thus to a rapid reduction of translational initiation and repression of global protein synthesis.
Gcn-2 of Caenorhabditis elegans
Receptor-interacting serine/threonine-protein kinase 3, RIPK3 of 518 aas and probably 0 TMSs. It modulates sarcoma through immune checkpoint HAVCR2 and regulates the TMC8 channel (TC# 1.A.17.4.11).
RIPK3 of Homo sapiens
Insulin-like growth factor 1 receptor (chain F) (IGF1R) of 952 aas, possibly with 4 N-terminal TMSs. It is antagonized by viral insulin/IGF-1-like peptides (e.g., VILP of 72 aas and no TMSs (Moreau et al. 2022).
IGF-1 of Homo sapiens
Leucine-rich repeat serine/threonine-protein kinase 2, LRRK2 or PARK8, of 2527 aas. Plays an important role in recruiting SEC16A to endoplasmic reticulum exit sites (ERES) and in regulating ER to Golgi vesicle-mediated transport and ERES organization (Cho et al. 2014). It positively regulates autophagy through calcium-dependent activation of the CaMKK/AMPK signaling pathway (Gómez-Suaga et al. 2012).
LRRK2 of Homo sapiens
Platelet-derived growth factor receptor-like protein, DPGFRL, of 375 aas. It is a biomarker for endometriosis (EM), a common gynecological disorder that often leads to irregular menstruation and infertility (Jiang et al. 2022).
DPGFRL of Homo sapiens
V-set and transmembrane domain-containing protein 2-like (VSTM2L) of 204 aas and 2 TMSs, N- and C-terminal. It is a crucial gene closely associated with ovarian cancer metastasis, progression, and prognosis (Li et al. 2023).
VSTM2L of Homo sapiens
Translation initiation factor 2-alpha kinase 3, PERK, of 1116 aas and at least 2 TMSs, one at the N-terminus and one at about residue 530. There are also three smaller peaks of hydrophobicity near the C-terminus of the protein that could be TMSs. It is a metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions. It is a key activator of the integrated stress response (ISR) required for adaptation to various stresses, such as the unfolded protein response (UPR) and low amino acid availability. EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activators ATF4 and QRICH1, and hence allowing ATF4- and QRICH1-mediated reprogramming (You et al. 2021). PERK/ATF3-reduced ER stress in a high potassium environment suppresses tumor ferroptosis (Pu et al. 2023).
PERK of Homo sapiens
Transmembrane and immunoglobulin domain-containing protein 1, TMIGD(1), isoform 2 precursor of 218 aas with 1 N-terminal TMS plus one possible TMS at about residue 120. The functions of TMIGD1 have been reviewed and include those of a tumor supressor and an adhesion receptor (Thüring et al. 2023; Mu et al. 2022). Macrophage-derived exosomes promote intestinal mucosal barrier dysfunction in inflammatory bowel disease by regulating TMIGD1 via mircroRNA-223 (Chang et al. 2023). Decreased TMIGD1 aggravates colitis and intestinal barrier dysfunction via the BANF1-NF-kappaB pathway in Crohn's disease (Zhou et al. 2023).
TMIGD1 of Homo sapiens
Roundabout homolog 2-like protein of 1319 aas and two TMSs, one at the N-terminus and one at about residues 880.
Roundabout2 of Anopheles merus
Fibroblast growth factor receptor-like protein, FGFRL1, of 504 aas and 2 TMSs, one N-terminal and one C-terminal. It is capable of inducing syncytium formation (Steinberg et al. 2010).
FGFRL-1 of Homo sapiens
Tyrosine-protein kinase transmembrane receptor, ROR1, of 937 aas and two TMSs, one at the N-terminus and one large hydrophobic peak at about residue 420. Extracellular vesicle-associated tyrosine kinase-like orphan receptors, ROR1 and ROR2, promote breast cancer progression (Irmer et al. 2023).
ROR1 of Homo sapiens
Uncharacterized protein of 412 aas and 2 TMSs, one N-terminal and one near the C-terminus. NOTE: This family may be homologous to families 8.A.128 and 9.B.454, do these three families may conprise a Superfamily.
UP of Dreissena polymorpha
Neural cell adhesion molecule L1, LICAM or CD171, of 1257 aas and 2 TMSs, N- and C-terminal. It is involved in the dynamics of cell adhesion and in the generation of transmembrane signals via tyrosine kinase receptors. During brain development, it is critical in multiple processes, including neuronal migration, axonal growth, fasciculation, and synaptogenesis. In the mature brain, it plays a role in the dynamics of neuronal structure and function, including synaptic plasticity (Schäfer et al. 2010). Interaction of L1CAM with LC3 is required for L1-dependent neurite outgrowth and neuronal survival (Loers et al. 2023).
LICAM of Homo sapiens
Fibroblast growth factor receptor 1, FGFR1, of822 aas and 2 TMSs, one N-terminal and one central. FGFR1 is a tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system (Haenzi and Moon 2017).
FGFR1 of Homo sapiens
Neuroplastin NptN of 398 aas (Beesley et al. 2014). Important for targetting of certain transporters such as Xkr8 to the plasma membrane with which it, with basigin, forms a physical complex (Suzuki et al. 2016). Neuroplastin expression is essential for hearing and hair cell PMCA (TC# 3.A.3.2.40) expression (Lin et al. 2021).
NptN of Homo sapiens
Fibroblast growth factor receptor 4, FGFR4, of 802 aas and 2 - 4 TMSs. Serves as the receptor for FGF23 for the activation of TRP6 (TC# 1.A.4.1.5). Binding activates the TRP6 channel for inorganic cation (including Ca2+) transport (Smith et al. 2017). It also regulates Na+:phosphate co-transport together with α-Klotho (see paragraph 2 in the family description of TC# 1.A.108; Hu et al. 2018).
FGFR4 of Homo sapiens
T-cell surface glycoprotein, CD4, of 458 aas and 2 TMSs, N- and C-terminal. It is the receptor for HIV and other viruses (see family description) (Raphael et al. 2020).
CD4 of Homo sapiens
CD4-like protein 2 of 429 aas and 2 TMSs, N- and C-terminal.
CD4 of Ctenopharyngodon idella (grass carp)
Lymphocyte activation gene 3 protein of 487 aas and 2 TMSs, one N-terminal and one C-terminal.
Lymphocyte activation protein of Thamnophis elegans (Western garter snake)
Neural cell adhesion molecule 2-like protein of 496 aas and 2 TMSs, N- and C-terminal.
Cell adhestion protein of Tachysurus fulvidraco (yellow cat fish)
Uncharacterized protein of 414 aas and 2 TMSs, N- and C-terminal.
UP of Colinus virginianus (northern bobwhite)
CD16A (FcγRIIIA, FCGR3A, FCG3, FCGR3, IGFR3) antiinflamatory protein of 254 aas and 2 TMSs, N- and C-terminal (Ben Mkaddem et al. 2014). It is a receptor for the Fc region of IgG. It binds complexed
or aggregated IgG and also monomeric IgG and mediates antibody-dependent
cellular cytotoxicity (ADCC) and other antibody-dependent responses,
such as phagocytosis (Ferrara et al. 2011, Mizushima et al. 2011).
CD16A of Homo sapiens
CD16B of 233 aas and 2 TMSs, N- and C-terminal. It may serve as a trap for immune complexes in the peripheral circulation which does not activate neutrophils. Microinflammation status, involving CD16, observed in chronic kidney disease patients is associated with endothelial damage (Ramirez et al. 2007). A 3-d cryoEM strcuture is available (Cai et al. 2022).
CD16B of Homo sapiens
TMEM25 of 366 aas and up to 4 TMSs, scattered throughout the protein. The expression of Tmem25 is strongly influenced by glutamate ionotropic receptor kainate type subunit 4, and it is primarily localized to late endosomes in neurons (Zhang et al. 2019). The effects of TMEM25 on neuronal excitability are likely mediated by N-methyl-D-aspartate receptors. TMEM25 affects the expression of the NR2B subunit and interacts with NR2B; both colocalize to late endosome compartments. TMEM25 induces acidification changes in lysosome compartments and accelerates the degradation of NR2B, and TMEM25 expression is decreased in brain tissues from patients with epilepsy and epileptic mice. TMEM25 overexpression attenuated the behavioral phenotypes of epileptic seizures, whereas TMEM25 downregulation exerted the opposite effect (Zhang et al. 2019). TMEM25 inhibits monomeric epidermal growth factor receptor (EGFR)-mediated STAT3 activation in the basal state to suppress triple-negative breast cancer progression (Bi et al. 2023).
TMEM25 of Homo sapiens
TMEM25-like protein, isoform X3 of 169 aas and 1 TMS.
TMEM25 of Pteropus alecto
TMEM25 protein of 279 aas and 1 TMS. It may be an incomplete sequence.
TMEM25 of Neopelma chrysocephalum (saffron-crested tyrant-manakin)
Intercellular adhesion molecule 1, ICAM-1 or ICAM1, of 532 aas and 2 TMSs, N- and C-terminal. During leukocyte trans-endothelial migration, ICAM1 engagement promotes the assembly of endothelial apical cups (Hayashi et al. 2001; van Buul et al. 2007). STAT3-dependent transcriptional regulation of ICAM-1, an endothelial transmembrane protein, regulates vascular permeability in endothelial cells (Wang et al. 2020). Martin et al. 2023 reviewed the role of ICAM-1 during both autoimmunity and islet graft rejection to understand the mechanism(s) leading to islet beta-cell death and dysfunction that results from insufficient circulating quantities of insulin to control glucose homeostasis.
ICAM1 of Homo sapiens
Vascular cell adhesion protein 1-like protein of 677 aas and probably two TMSs, N- and C-terminal.
Vascular cell adhesion protein 1 of Bufo bufo (common toad)
Hemicentin-1 of 590 aas and possibly two TMSs, one N-terminal and one near the C-terminus of the protein. Hemicentins are conserved extracellular matrix proteins discovered in Caenorhabditis elegans, with orthologs in all vertebrate species including humans (Vogel et al. 2006).
Hemicentin 1 of Sander lucioperca (pikeperch)
Programmed cell death 1 ligand 1, PDL1, CD274, B7H1, PDCD1L1, or PDCD1LG1, of 290 aas and 2 TMSs, one N-terminal and one C-terminal. It plays a role in induction of immune tolerance to self. It plays a critical role in induction and maintenance of immune tolerance to self (Freeman et al. 2000, Burr et al. 2017, Mezzadra et al. 2017). As a ligand for the inhibitory receptor PDCD1/PD-1, it modulates the activation threshold of T-cells and limits T-cell effector responses. Several forms of PD-L1 exist expressed on the plasma membrane (mPD-L1), at the surface of secreted cellular exosomes (exoPD-L1), in cell nuclei (nPD-L1), or as a circulating, soluble protein (sPD-L1) (Bailly et al. 2021). The membrane, exosomal and soluble forms of PD-L1 are parts of the highly dynamic PD-1/PD-L1 signaling pathway. PD-L1 translocation to the plasma membrane enables tumor immune evasion through MIB2 ubiquitination (Yu et al. 2023).
PD-L1 of Homo sapiens
V-set domain-containing T-cell activation inhibitor 1 of 282 aas and 2 TMSs, N- and C-terminal.
V-set domain containing protein of Pteropus giganteus (Indian flying fox)
Butyrophilin-like protein 2 of 487 aas and 2 TMSs, N- and C-terminal.
Butyrophilin of Lynx canadensis (canadian lynx)