MAIN RTKs

Ligand binding is inhibited by suramin, a hexasulfonated naphthylurea compound of 1429 Da that was used initially as a drug for the treatment of trypanosomiasis :

Ligand-induced receptor dimerization (only InsR is already dimerized before ligand binding !) is inhibited by :

Dimerization triggers reciprocal autophosphorylation of the CTD of b chains and of phosphotyrosine (pY) motifs of IRS-1 and IRS-2 : pYs then act as binding site for SH2-containing proteins.
Some SH2 domain-containing proteins bind only phosphotyrosine motifs on b chains (e.g. PL-Cg), others only those on IRSs.
The induction of MKP-1 removes the negative feedback of MAPKs on Sos => biphasic responses.
Click here for their signal tranduction pathway (STP).
Common biological outputs :
RTK name

expressed on ...
ligand(s)
agonists
antagonists
CD220 / InsR (also activates STAT1 and STAT3)
brain neurons (including arcuate nucleus) insulin

CD221 / IGF-1R

NSILA(S)-1 / SM-C / IGF-1
inhibitor of the IGF-IR kinaseref
  • NVP-AEW541 (27-fold more potent against IGF1R that against InsR)
  • NVP-ADW742
CD115 / M-CSFR / CSF-1R (also activates STAT3 and STAT5)
monocytes, macrophages M-CSF / CSF-1
IL-34


HGF receptor / c-Met
epithelial cells and melanocytes HGF / scatter factor
neurturin


tyrosine kinase with immunoglobulin and epidermal growth factor 1 (Tie-1 / TIE)

Ang-1
Ang-2
Ang-3
Ang-4


CD202b / tyrosine kinase with immunoglobulin and epidermal growth factor 1 (Tie-2)

Ang-1
Ang-2
Ang-3
Ang-4


FGFR1 / fms2 (9 isoforms) (also activates STAT3)

FGF/HBGF 1-23, including FGF-1 / aFGF, FGF2 / bFGF, FGF-7 / KGF, ...
nintedanib / BIBF 1120 (Vargatef®; triple angiokinase inhibitor that also simultaneously acts on VEGFR and PDGFR)
FGFR2 (13 isoforms) (also activates STAT3)

FGF/HBGF 1-23, including FGF-1 / aFGF, FGF2 / bFGF, FGF-7 / KGF, ...

FGFR3 (2 isoforms) (also activates STAT3)

FGF/HBGF 1-23, including FGF-1 / aFGF, FGF2 / bFGF, FGF-7 / KGF, ...

FGFR4 (2 isoforms) (also activates STAT3)

FGF/HBGF 1-23, including FGF-1 / aFGF, FGF2 / bFGF, FGF-7 / KGF, ...

FLT-1 / VEGFR1

VEGF-A121, 165, 189 or 206
PlGF
VEGF-B

  • SU11248
  • PTK787/ZK222584 (PTK/ZK)
  • AZD2171 (Recentin®; source : AstraZeneca)
  • motesanib diphosphate / AMG 706
  • pazopanib / GW786034 (Votrient®)
  • nintedanib / BIBF 1120 (Vargatef®; triple angiokinase inhibitor that also simultaneously acts on PDGFR and FGFR)
  • FLT-3
    a high proportion of acute myeloid leukemia (AML) and B-lineage acute lymphocytic leukemia (ALL) cells, hematopoietic stem cells (HSCs), brain, placenta and liver FLT3L progenipoietin-4 (ProGP-4) (also for G-CSFR)
  • CT53518 
  • PKC412 
  • SU11248
  • MR22388
  • VX-680
  • crenolanib besylate / CP-868596
  • lestaurtinib / CEP-701 (source : Cephalon)
  • sorafenib / BAY 43-9006 (Nexavar®; source : Bayer AG and Onyx Pharmaceuticals Inc) (also an inihibitor of VEGFR2, c-KIT and RAF1ref)
  • imidazoacridinones :
  • FLK-1 / VEGFR2 / KDR

    VEGF-A121, 165, 189 or 206
    VEGF-C
    VEGF-D
    VEGF-E

  • PTK787/ZK222584 (PTK/ZK) 
  • ZD6474 
  • AZD2171, orally bioavailableref
  • BAY 43-9006 / sorafenib (Nexavar®; source :  Bayer AG and Onyx Pharmaceuticals Inc) (also an inihibitor of VEGFR2, c-KIT and RAF1ref)
  • motesanib diphosphate / AMG 706
  • pazopanib / GW786034 (Votrient®)
  • YM-359445, an orally bioavailableref
  • FLT-4 / VEGFR3
    lymphatic endothelial cells VEGF-C
    VEGF-D

  • BAY 43-9006 / sorafenib
  • motesanib / AMG 706
  • pazopanib / GW786034 (Votrient®)
  • ERBB1 / c-ERBB / EGF receptor (EGFR) / HER-1 (needs cleavage on the ECM side by ADAM to be activated; also activates STAT1, STAT3, and STAT5)

    EGF
    TGFa
    betacellulin
    neuregulin 1

    gefitinib / ZD1839 (Iressa©; IC50 = 0.023-0.069 mM; IC50 for ligand-induced cell growth = 0.080 mM; source : AstraZeneca; side effect : interstitial pneumonia
    erlotinib / OSI-774 (Tarceva©; source : Genentech)
    lapatinib / EGF105084 (Tykerb©; source : GSK)
    ZD6474 
    CI1033 
    GW572016 
    PKI166 
    EKB-569
    leflunomide (Arava©) and it's metabolite, A771726 / teriflunomide
    ERBB2 / NEU / HER-2 (to function it must dimerize with another member of the ERBB family)

    neuregulin 1 (binds ERBB2 / ERBB3 heterodimer)
    gefitinib
    lapatinib
    GW572016 
    PKI166 
    ERBB3 / HER-3 (decoy receptor as it lacks Tyr kinase activity)

    neuregulin 1 (binds ERBB2 / ERBB3 heterodimer)
    neuregulin 2


    ERBB4 / HER-4

    betacellulin
    neuregulin 1
    neuregulin 2
    intramembrane binding with the transmembrane domain of ASGP2


    PDGFR (multimeric : CD140a / a + CD140b / b) (also activates STAT1, STAT3, and STAT5)

    PDGF
  • CT53518
  • PKC412
  • SU11248
  • imatinib mesylate / STI 571 (Gleevec / Glivec©
  • sunitinib malate / SU11248 (Sutent©; source : Sugen)
  • motesanib diphosphate  / AMG 706
  • pazopanib / GW786034 (Votrient®)
  • nintedanib / BIBF 1120 (Vargatef®; triple angiokinase inhibitor that also simultaneously acts on VEGFR and FGFR)
  • BAY 43-9006 / sorafenib
  • relaxin receptor

    RLX1
    RLX2
    RLX3


    CD117 / c-KIT

    SCF
  • CT53518 
  • PKC412 
  • SU11248 
  • imatinib mesylate / STI 571 (Gleevec / Glivec©)
  • motesanib diphosphate  / AMG 706
  • BAY 43-9006 / sorafenib (Nexavar®; source :  Bayer AG and Onyx Pharmaceuticals Inc) (also an inihibitor of VEGFR2, c-KIT and RAF1ref)
  • pazopanib / GW786034 (Votrient®
  • TRK family members are variably expressed throughout the central and peripheral nervous systems TrkA / neurotrophic tyrosine kinase, receptor, type 1 autophosphorylates on tyrosine residues (Tyr490, Tyr674, Tyr675, Tyr751, and Tyr785)
    neurotrophins / neurotrophic factors : 

    TrkB pre- and postsynaptic neurons of excitatory synaptic transmission in the CA1 region of the hippocampus neurotrophins / neurotrophic factors : 

    TrkC
    neurotrophins / neurotrophic factors : 

    TrkE / discoidin domain receptor family, member 1



    p75NTR

    neurotrophins / neurotrophic factors : 

    RET
    nociceptors neurotrophins / neurotrophic factors : 

    receptor for advanced glycation endproducts (RAGE) (needs cleavage on the ECM side by an ADAM to be activated)
    peripheral neurons, vascular endothelial cells and pericytes, synovial fibroblasts 
  • b amyloid fibrils 
  • amphiregulin 
  • S100 / calgranulins 
  • advanced glycation end-products (AGEs)
  • high-mobility group B1 protein (HMGB1)


  • muscle-specific kinase (MuSK)
    early myotomes and developing muscle,  then dramatically down-regulated in mature muscle, where it remains prominent only at the NMJ (the only known RTK that localizes to the NMJ); induced throughout the adult myofiber after denervation, block of electrical activity, or physical immobilization. agrin

    anaplastic lymphoma kinase (Alk)

    Jelly belly (Jeb)




    amphoterin

    EPH receptors typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. They are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. EphA1
    Ephrin-A1
    Ephrin-A2
    Ephrin-A3
    Ephrin-A4
    Ephrin-A5


    EphA2
    Ephrin-A1
    Ephrin-A2
    Ephrin-A3
    Ephrin-A4
    Ephrin-A5


    EphA3
    Ephrin-B2

    EphA4
    Ephrin-A1
    Ephrin-A2
    Ephrin-A3
    Ephrin-A4
    Ephrin-A5


    EphA5
    Ephrin-A1
    Ephrin-A2
    Ephrin-A3
    Ephrin-A4
    Ephrin-A5


    EphA7
    Ephrin-A1
    Ephrin-A2
    Ephrin-A3
    Ephrin-A4
    Ephrin-A5


    EphA8
    Ephrin-A2
    Ephrin-A3
    Ephrin-A5


    EphB1
    Ephrin-B1
    Ephrin-B2
    Ephrin-B3


    EphB2
    Ephrin-B1
    Ephrin-B2
    Ephrin-B3


    EphB3
    Ephrin-B1
    Ephrin-B2
    Ephrin-B3


    EphB4
    Ephrin-B2

    EphB6 (decoy receptor : lacks the kinase activity)
    Ephrin-B1
    Ephrin-B2
    Ephrin-B3


    Membrane-bound receptors generate soluble ligand binding domains either by proteolytic cleavage of the extracellular domain or alternative mRNA splicing yielding a secreted protein. MERTK is in a receptor tyrosine kinase family with Axl and Tyro-3, and all 3 receptors share the Gas6 ligand. Mer regulates macrophage activation, promotes apoptotic cell engulfment, and supports platelet aggregation and clot stability in vivo. The membrane-bound Mer protein is cleaved in the extracellular domain via a MMP. The cleavage results in the production of a soluble Mer protein released in a constitutive manner from cultured cells. Significant amounts of the soluble Mer protein were also detected in human plasma, suggesting its physiological relevance. Cleavage of Mer was enhanced by treatment with LPS and PMA, and was specifically inhibited by a TNF  converting enzyme metalloprotease inhibitor. As a decoy for Gas6, soluble Mer prevented Gas6 mediated stimulation of membrane-bound Mer. The inhibition of Gas6 activity by soluble Mer led to defective macrophage-mediated engulfment of apoptotic cells. Furthermore, soluble Mer decreased platelet aggregation in vitro and prevented fatal collagen/epinephrine induced thromboembolism in mice, suggesting a potential therapeutic use for soluble Mer in the treatment of clotting disordersref
















    The FGF signaling pathway
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