Table 1.
Cytoplasmic signaling (effector) domains of various cell receptors studied in this work
| Receptor/signaling subunita | Functional roleb | Swiss-Prot accession numberc | alpha-MoRF predictiond |
| Single-chain receptors | |||
| Receptor tyrosine kinases | |||
| ErbB-1 | Receptor for EGF but also for other members of the EGF family, as TGFalpha, amphiregulin, betacellulin, heparin-binding EGF-like growth factor, GP30 and vaccinia virus growth factor. Control of cell growth and differentiation. |
P00533 (669–210) |
1–18 385–402 414–431 |
| ErbB-2 | Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Binds to the MT-CO2 promoter and activates its transcription. |
P04626 (676–1255) |
370–387 409–426 500–517 |
| ErbB-3 | Binds and is activated by neuregulins and NTAK. |
P21860 (665–1342) |
1–18 555–572 595–612 |
| ErbB-4 | Specifically binds and is activated by neuregulins, heparin-binding EGF-like growth factor, betacellulin and NTAK. Interaction with these factors induces cell differentiation. Not activated by EGF, TGF-A and amphiregulin. |
Q15303 (676–1308) |
351–368 424–441 612–629 |
| PDGFR-A | Receptor that binds both PDGFA and PDGFB and has a tyrosine-protein kinase activity. |
P16234 (550–1089) |
523–540 |
| PDGFR-B | Receptor that binds specifically to PDGFB and PDGFD and has a tyrosine-protein kinase activity. Phosphorylates Tyr residues at the C-terminus of PTPN11 creating a binding site for the SH2 domain of GRB2. |
P09619 (557–1106) |
451–468 |
| FGFR-1 | Receptor for basic fibroblast growth factor. Receptor for FGF23 in the presence of KL. |
P11362 (398–822) |
10–27 |
| FGFR-2 | Receptor for acidic and basic fibroblast growth factors. |
P21802 (399–821) |
- |
| FGFR-3 | Receptor for acidic and basic fibroblast growth factors. Preferentially binds FGF1. |
P22607 (397–806) |
15–32 |
| FGFR-4 | Receptor for acidic fibroblast growth factor. Does not bind to basic fibroblast growth factor. Binds FGF19. |
P22455 (391–802) |
16–33 |
| VEGFR-1 | Receptor for VEGF, VEGFB and PGF. The VEGF-kinase ligand/receptor signaling system plays a key role in vascular development and regulation of vascular permeability. |
P17948 (781–1338) |
522–539 |
| VEGFR-2 | Receptor for VEGF or VEGFC. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions. |
P35968 (790–1356) |
167–184 485–502 525–542 |
| VEGFR-3 | Receptor for VEGFC. |
P35916 (798–1298) |
151–168 183–200 455–472 |
| HGFR | Receptor for hepatocyte growth factor and scatter factor. Functions in cell proliferation, scattering, morphogenesis and survival. |
P08581 (956–1390) |
10–27 |
| Trk-A | Required for high-affinity binding to NGF, neurotrophin-3 and neurotrophin-4/5 but not BDNF. Known substrates for the TRK receptors are SHC1, PI3-kinase, and PLCgamma-1. Has a crucial role in the development and function of the nociceptive reception system as well as establishment of thermal regulation via sweating. Activates ERK1 by either SHC1- or PLC-gamma-1-dependent signaling pathway. |
P04629 (440–796) |
- |
| Trk-B | Receptor for BDNF, neurotrophin-3 and neurotrophin-4/5 but not NGF. Involved in the development and/or maintenance of the nervous system. Known substrates for the TRK receptors are SHC1, PI-3 kinase and PLCgamma-1. |
Q16620 (455–822) |
- |
| Trk-C | Receptor for NT-3. Known substrates for the Trk receptors are SHC1, PI-3 kinase and PLCG1. The different isoforms do not have identical signaling properties. |
Q16288 (454–839) |
- |
| LTK | The exact function of this protein is not known. |
P29376 (450–864) |
1–18 372–389 398–415 |
| Tie-1 | The exact function of this protein is not known. |
P35590 (785–1138) |
- |
| Tie-2 | Receptor for angiopoietin 1. It may constitute the earliest mammalian endothelial cell lineage marker. Probably regulates endothelial cell proliferation, differentiation and guides the proper patterning of endothelial cells during blood vessel formation. |
Q02763 (771–1124) |
- |
| ROR1 | Functional role is not yet clear. |
Q01973 (428–937) |
1–18 27–44 315–332 376–393 |
| ROR2 | May be involved in the early formation of the chondrocytes. It seems to be required for cartilage and growth plate development. Phosphorylates YWHAB, leading to induction of osteogenesis and bone formation. |
Q01974 (425–943) |
1–18 30–47 366–383 401–418 502–519 |
| DDR1 | Interacts (via PPxY motif) with WWC1 (via WW domains) in a collagen-regulated manner. Forms a tripartite complex with WWC1 and PRKCZ, but predominantly in the absence of collagen. May be involved in cell-cell interactions and recognition. |
Q08345 (444–913) |
1–18 59–76 92–109 126–143 |
| DDR2 | Receptor for fibrillar collagen mediates fibroblast migration and proliferation. Contributes to cutaneous wound healing. |
Q16832 (422–855) |
1–18 47–64 |
| RYK | Potential growth factor receptor protein tyrosine kinase. |
P34925 (253–604) |
1–18 |
| MuSK | Key mediator of agrin's action and is involved in NMJ organization. |
O15146 (517–869) |
11–28 |
| INSR | Binds insulin. Mediates the metabolic functions of insulin. Binding to insulin stimulates association of the receptor with downstream mediators including IRS1 and PI3K. Can activate PI3K either directly by binding to the p85 regulatory subunit, or indirectly via IRS1. |
P06213 (980–1382) |
362–379 |
| C-Ret receptor | Probable receptor with tyrosine-protein kinase activity. Important for development. |
P07949 (658–1114) |
356–373 |
| EPHA-1 | Receptor for members of the ephrin-A family. Binds with a low affinity to ephrin-A1. |
P21709 (569–976) |
- |
| EPHA-2 | Receptor for members of the ephrin-A family. Binds to ephrin-A1, -A3, -A4 and -A5. Plays an important role in angiogenesis and tumor neovascularization. |
P29317 (559–976) |
- |
| EPHA-3 | Receptor for members of the ephrin-A family. Binds to ephrin-A2, -A3, -A4 and -A5. Could play a role in lymphoid function. |
P29320 (566–983) |
- |
| EPHA-4 | Receptor for members of the ephrin-A family. Binds to ephrin-A1, -A4 and -A5. May play a role in a signal transduction process involved in hindbrain pattern formation. |
P54764 (570–986) |
- |
| EPHA-5 | Receptor for members of the ephrin-A family. Binds to ephrin-A1, -A2, -A3, -A4 and -A5. |
P54756 (595–1037) |
- |
| EPHA-6 | Receptor for members of the ephrin-A family. |
Q9UF33 (571–1035) |
- |
| EPHA-7 | Receptor for members of the ephrin-A family. Binds to ephrin-A1, -A2, -A3, -A4 and -A5. |
Q15375 (578–998) |
- |
| EPHA-8 | Receptor for members of the ephrin-A family. Interacts with FYN. Interacts with ANKS1B. |
P29322 (564–1005) |
19–36 |
| EPHA-10 | Receptor for members of the ephrin-A family. Binds to ephrin-A3, -A4 and -A5. |
Q5JZY3 (587–1008) |
- |
| EPHB-1 | Receptor for members of the ephrin-B family. Binds to ephrin-B1, -B2 and -B3. May be involved in cell-cell interactions in the nervous system. |
P54762 (564–984) |
- |
| EPHB-2 | Receptor for members of the ephrin-B family. Acts as a tumor suppressor. |
P29323 (565–1055) |
474–491 |
| EPHB-3 | Receptor for members of the ephrin-B family. Binds to ephrin-B1 and -B2. |
P54753 (581–998) |
- |
| EPHB-4 | Receptor for members of the ephrin-B family. Binds to ephrin-B2. May have a role in events mediating differentiation and development. |
P54760 (561–987) |
- |
| EPHB-6 | Kinase-defective receptor for members of the ephrin-B family. Binds to ephrin-B1 and ephrin-B2. Modulates cell adhesion and migration. |
O15197 (601–1006) |
- |
| TNF receptors | |||
| TNF-R1 | Receptor for TNFSF2/TNFalpha and homotrimeric TNFSF1/lymphotoxin-alpha. Contributes to the induction of non-cytocidal TNF effects including anti-viral state and activation of the acid sphingomyelinase. |
P19438 (235–455) |
188–205 |
| TNF-R2 | Receptor with high affinity for TNFSF2/TNFalpha and approximately 5-fold lower affinity for homotrimeric TNFSF1/lymphotoxin-alpha. Mediates most of the metabolic effects of TNFalpha. |
P20333 (288–461) |
1–18 91–108 |
| TNF-R3 (LTBR) | Receptor for the heterotrimeric lymphotoxin containing LTA and LTB, and for TNFS14/LIGHT. Promotes apoptosis via TRAF3 and TRAF5. May play a role in the development of lymphoid organs. |
P36941 (249–435) |
30–47 158–175 |
| TNF-R4 | Receptor for TNFSF4/OX40L/GP34. Interacts with TRAF2, TRAF3 and TRAF5. |
P43489 (236–277) |
1–18 25–42 |
| TNF-R5 | Receptor for TNFSF5/CD40LG. Interacts with TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6 |
P25942 (216–277) |
5–22 |
| TNF-R6 (FAS receptor) | Receptor for TNFSF6/FASLG. FAS-mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen-stimulated suicide of mature T cells, or both. |
P25445 (191–335) |
1–18 |
| TNF-R7 | Receptor for CD70/CD27L. Interacts with SIVA1 and TRAF2. May play a role in survival of activated T cells. May play a role in apoptosis. |
P26842 (213–260) |
1–18 |
| TNF-R8 | Receptor for TNFSF8/CD30L. Interacts with TRAF1, TRAF2, TRAF3 and TRAF5. May play a role in the regulation of cellular growth and transformation of activated lymphoblasts. Regulates gene expression. |
P28908 (408–595) |
6–23 104–121 |
| TNF-R9 | Receptor for TNFSF14/4-1BBL. Interacts with TRAF1, TRAF2 and TRAF3. Interacts with LRR-repeat protein 1/LRR-1. Possibly active during T cell activation. |
Q07011 (214–255) |
6–23 |
| TNF-R10A | Receptor for the cytotoxic ligand TNFSF10/TRAIL. Can interact with TRADD and RIPK1. Interacts with ARAP1. Promotes the activation of NFkappaB. |
O00220 (263–468) |
- |
| TNF-R10B | Receptor for the cytotoxic ligand TNFSF10/TRAIL. Can interact with TRADD and RIPK1. Promotes the activation of NFkappaB. |
O14763 (232–440) |
- |
| TNF-R10D | Receptor for the cytotoxic ligand TRAIL. It is not capable of inducing apoptosis but protects against TRAIL-mediated apoptosis. Reports are contradictory with regards to its ability to induce the NFkappaB pathway. |
Q9UBN6 (233–386) |
29–46 94–111 127–144 |
| TNF-R11A (RANK) | Receptor for TNFSF11/RANKL/TRANCE/OPGL. Interacts with TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6. Interacts (via cytoplasmic domain) with GAB2. Essential for RANKL-mediated osteoclastogenesis. |
Q9Y6Q6 (234–616) |
256–273 301–318 341–358 |
| TNF-R12A | Receptor for TNFSF12/TWEAK. Associates with TRAF1 and TRAF2, and probably also with TRAF3. Weak inducer of apoptosis in some cell types. Promotes angiogenesis and the proliferation of endothelial cells. |
Q9NP84 (102–129) |
- |
| TNF-R13B | Receptor for TNFSF13/APRIL and TNFSF13B/TALL1/BAFF/BLYS that binds both ligands with similar high affinity. Binds TRAF2, TRAF5 and TRAF6. Binds the NH2-terminal domain of CAMLG with its C-terminus. Involved in the stimulation of B- and T cell function and the regulation of humoral immunity. |
O14836 (187–293) |
1–18 44–61 |
| TNF-R13C | B-cell receptor specific for TNFSF13B/TALL1/BAFF/BLyS. Promotes the survival of mature B-cells and the B-cell response. |
Q96RJ3 (100–184) |
1–18 68–85 |
| TNF-R14 | Receptor for BTLA. Receptor for TNFSF14/LIGHT and homotrimeric TNFSF1/lymphotoxin-alpha. Involved in lymphocyte activation. Interacts with TRAF2, TRAF3 and TRAF5. Interacts with HHV-1 and HHV-2 envelope glycoprotein D. Functions as an entry receptor for these viruses. Enhances the entry of several wild-type HSV strains of both serotypes into CHO cells and mediates HSV entry into activated human T cells. |
Q92956 (224–283) |
- |
| TNF-R16 (NGF receptor) | Low affinity receptor which can bind to NGF, BDNF, NT-3 and NT-4. Interacts with p75NTR-associated cell death executor. Interacts with TRAF2, TRAF4, TRAF6, PTPN13 and RANBP9. Interacts with LINGO1. Can mediate cell survival as well as cell death of neural cells. |
P08138 (273–427) |
1–18 |
| TNF-R17 | Receptor for TNFSF13B/BLyS/BAFF and TNFSF13/APRIL. Associates with TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6. Promotes B-cell survival and plays a role in the regulation of humoral immunity. Activates NFkappaB and JNK. |
Q02223 (78–184) |
62–79 |
| TNF-R18 | Receptor for TNFSF18. Binds to TRAF1, TRAF2 and TRAF3, but not TRAF5 and TRAF6. Binds through its C-terminus to SIVA1/SIVA. Seems to be involved in interactions between activated T-lymphocytes and endothelial cells and in the regulation of TCR-mediated cell death. Mediates NFkappaB activation via the TRAF2/NIK pathway. |
Q9Y5U5 (184–241) |
3–20 41–58 |
| TNF-R19 | Associates with TRAF1, TRAF2, TRAF3 and TRAF5. Interacts with LINGO1. Can mediate activation of JNK and NFkappaB. May promote caspase-independent cell death. |
Q9NS68 (192–423) |
172–189 |
| TNF-R21 | Associates with TRADD. Interacts with N-APP. May activate NFkappaB and promote apoptosis. May activate JNK and be involved in T-cell differentiation. Required for both normal cell body death and axonal pruning. |
O75509 (371–655) |
162–179 |
| TNF-R25 | Receptor for TNFSF12/APO3L/TWEAK. Interacts directly with the adapter TRADD. Interacts with BAG4. Mediates activation of NFkappaB and induces apoptosis. May play a role in regulating lymphocyte homeostasis. |
Q93038 (221–417) |
- |
| TNF-R27 (EDA-A2 receptor) | Receptor for EDA isoform A2, but not for EDA isoform A1. Associates with TRAF1, TRAF3 and TRAF6. Mediates the activation of the NFkappaB and JNK pathways. |
Q9HAV5 (160–297) |
11–28 50–67 82–99 |
| Type I Cytokine Receptors | |||
| EpoR | Receptor for erythropoietin. Mediates erythropoietin-induced erythroblast proliferation and differentiation. Triggers the JAK2/STAT5 signaling cascade. In some cell types, can also activate STAT1 and STAT3. May also activate the LYN tyrosine kinase. |
P19235 (274–508) |
90–107 165–182 218–235 |
| G-CSF-R | Receptor for granulocyte colony-stimulating factor (CSF3), essential for granulocytic maturation. Plays a crucial role in the proliferation, differentiation and survival of cells along the neutrophilic lineage. May function in some adhesion or recognition events at the cell surface. |
Q99062 (651–836) |
20–37 52–69 |
| GM-CSF/IL-3/IL-5 receptor common beta-chain | High affinity receptor for IL-3, IL-5 and granulocyte-macrophage colony-stimulating factor. The beta subunit is common to the IL-3, IL-5 and GM-CSF receptors. |
P32927 (461–897) |
48–65 122–139 166–183 252–269 355–372 |
| Growth hormone receptor | Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. On ligand binding, couples to the JAK2/STAT5 pathway. The soluble form (GHBP) acts as a reservoir of growth hormone in plasma and may be a modulator/inhibitor of GH signaling. |
P10912 (289–638) |
93–110 131–148 189–206 |
| Prolactin receptor | Receptor for the anterior PRL. Interacts with SMARCA1. Interacts with GH1. Interacts with CSH. Isoform 4 is unable to transduce prolactin signaling. Isoform 6 is unable to transduce prolactin signaling. |
P16471 (259–622) |
67–84 111–128 138–155 180–197 239–256 |
| Type II Cytokine Receptors | |||
| IFNgamma receptor alpha-chain | Receptor for IFNgamma. Two receptors bind one IFNgamma dimer. |
P15260 (267–489) |
135–152 |
| IFNgamma receptor beta-chain | Part of the receptor for IFNgamma. Required for signal transduction. This accessory factor is an integral part of the IFNgamma signal transduction pathway and is likely to interact with GAF, JAK1 and/or JAK2. |
P38484 (269–337) |
40–57 |
| IFNalpha/beta receptor alpha-chain | Associates with IFNAR2 to form the type I IFN receptor. Receptor for IFNsalpha and beta. Interacts with IFNAR2. Binding to type I IFNs triggers tyrosine phosphorylation of a number of proteins including JAKs, TYK2, STAT proteins and IFNRalpha- and beta-subunits themselves. |
P17181 (458–557) |
61–78 |
| IFNalpha/beta receptor beta-chain | Associates with IFNAR1 to form the type I IFN receptor. Receptor for IFNalpha and beta. Involved in IFNmediated STAT1, STAT2 and STAT3 activation. Isoform 1 and isoform 2 are directly involved in signal transduction due to their association with the TYR kinase, JAK1. Isoform 3 is a potent inhibitor of type I IFN receptor activity. |
P48551 (265–515) |
157–174 234–251 |
| TGFbeta receptors | |||
| TGFbeta type I receptor | On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Interacts with CD109 and RBPMS. Interacts with SMAD2 when phosphorylated on several residues in the GS region. Interacts with TRAF6. Receptor for TGFbeta. |
P36897 (148–503) |
- |
| TGFbeta type II receptor | On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Binds to DAXX. Interacts with TCTEX1D4. Receptor for TGFbeta. |
P37173 (188–567) |
363–380 |
| Other single chain receptors | |||
| Beta-2 AR | Binds SLC9A3R1 and GPRASP1. Interacts with ARRB1 and ARRB2. Interacts with SRC, USP20 and USP33. Mediates the catecholamine-induced activation of adenylate cyclase through the action of G proteins. Binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine. |
P07550 (59–71) (130–150) (221–274) (330–413) |
- - 18–35 34–51 63–80 |
| Multichain receptors | |||
| T cell receptor | |||
| Zeta | Contains 3 ITAM domains. Plays a role in assembly and expression of the TCR complex as well as signal transduction upon antigen triggering. Interacts with SLA and SLA2. Interacts with DOCK2 and TRAT1. Interacts with HIV-1and HIV-2 Nef protein; this interaction induces downregulation of cell surface TCR/CD3 complexes. |
P20963 (52–164) |
18–35 58–75 |
| CD3epsilon | Contains 1 ITAM domain. Mediates signal transduction. |
P07766 (153–207) |
- |
| CD3delta | Contains 1 ITAM domain. Mediates signal transduction. |
P04234 (127–171) |
15–32 |
| CD3gamma | Contains 1 ITAM domain. Mediates signal transduction. |
P09693 (138–182) |
22–39 |
| B cell receptor | |||
| Igalpha | Contains 1 ITAM domain. Mediates signal transduction. Required for BCR surface expression and for efficient differentiation of pro- and pre-B-cells. Stimulates SYK autophosphorylation and activation. Binds to BLNK. Represses BCR signaling during development of immature B cells. |
P11912 (166–226) |
24–41 |
| Igbeta | Contains 1 ITAM domain. Mediates signal transduction. Enhances phosphorylation of Ig alpha. |
P40259 (181–229) |
- |
| Fc receptors | |||
| Fcepsilon RI beta chain | Signaling subunit of Fcepsilon type I receptor (Fcepsilon RI). Contains 1 ITAM domain (in: 201–244). Mediates signal transduction and initiation of the allergic response. |
Q01362 (1–59) (118–130) (201–244) |
42–59 - - |
| FcRgamma chain | Signaling subunit of Fc epsilon RI and other Fc receptors. Contains 1 ITAM domain. Mediates signal transduction. Regulates several aspects of the immune response. |
P30273 (45–86) |
- |
| Other multichain receptors | |||
| DAP-10 | Signaling subunit of NKG2D and other multichain receptors. Contains 1 tyrosine-phosphorylated YINM motif. Mediates signal transduction. |
Q9UBK5 (70–93) |
- |
| DAP-12 | Signaling subunit of TREM-1 and other multichain receptors. ITAM domain. Mediates signal transduction. |
O43914 (62–113) |
- |
a
For multichain receptors including MIRRs.
b
As provided in the Swiss-Prot database [Bairoch A, et al. The Universal Protein Resource (UniProt). Nucleic Acids Res 2005; 33:154–9].
c
Numbers in parentheses are amino acid residues of cytoplasmic domain.
d
Amino acid residues. Predicted using the algorithms described in Mohan A, et al. Analysis of molecular recognition features (MoRFs). J Mol Biol 2006; 362:1043–59.
Abbreviations: MIRR, multichain immune recognition receptor; alpha-MoRF, alpha-Helix-forming Molecular Recognition Feature; EGF, epidermal growth factor; TGF, transforming growth factor; GP, glycoprotein; NTAK, neural- and thymus-derived activator for ErbB kinases; PDGFR, platelet-derived growth factor receptor; PTPN11, the SH2-containing tyrosine phosphatase Shp2; GRB2, growth factor receptor-bound protein 2; FGFR, fibroblast growth factor receptor; KL, Klotho; VEGFR, vascular endothelial growth factor receptor; MuSK, muscle specific kinase; PGF, prostaglandin F; HGFR, hepatocyte growth factor receptor; TRK, tyrosine kinase receptor; NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; SHC, Src homologous and collagen protein; PI, phosphatidylinositol; PLC, phospholipase C; ERK, extracellular signal-regulated kinase; NT, neurotrophin; LTK, leukocyte tyrosine kinase; ROR, receptor tyrosine kinase-like orphan receptor; YWHAB, the beta polypeptide of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein; DDR, discoidin domain receptor; WWC, WW domain-containing protein; PRKCZ, protein kinase Czeta; MuSK; muscle-specific kinase; NMJ, neuromuscular junction; INSR, insulin receptor; IRS, insulin receptor substrate; PI3K, phosphatidylinositol 3′-kinase; EPH, ephrin; TNF, tumor necrosis factor; LTBR, lymphotoxin-b receptor; TRAF, tumor necrosis factor receptor-associated factor; LRR, leucine-rich repeat; RANK, receptor activator of NFκB; HSV, herpes simplex virus; HHV, human herpes virus; TCR, T cell receptor; EDA, ectodermal dysplasin; EpoR, erythropoietin receptor; G-CSF-R, granulocyte colony-stimulating factor receptor; IL, interleukin; GMCSF, granulocyte-macrophage colony stimulating factor; GHBP, growth hormone binding protein; PRL, pituitary hormone prolactin; CsH, cyclosporin H; IFN, interferon; TGF, transforming growth factor; AR, adrenergic receptor; ITAM, immunoreceptor tyrosine-based activation motif; HIV, human immunodeficiency virus; Ig, immunoglobulin; BCR, B cell receptor; DAP-12, DNAX-activating protein of molecular mass 12 kilodaltons; TREM-1, triggering receptor expressed on myeloid cells 1.