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 (ligand(s))
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
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, ...
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)
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 
VX-680
BAY 43-9006 / sorafenib (Nexavar®; source :  Bayer AG and Onyx Pharmaceuticals Inc) (also an inihibitor of VEGFR2, c-KIT and RAF1ref)
FLK-1 / VEGFR2 / KDR VEGF-A121, 165, 189 or 206
VEGF-C
VEGF-D
VEGF-E		 PTK787/ZK222584 (PTK/ZK) 
ZD6474 
BAY 43-9006 / sorafenib (Nexavar®; source :  Bayer AG and Onyx Pharmaceuticals Inc) (also an inihibitor of VEGFR2, c-KIT and RAF1ref)
FLT-4 / VEGFR3 lymphatic endothelial cells VEGF-C
VEGF-D		 BAY 43-9006 / sorafenib
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
ZD6474 
CI1033 
GW572016 
PKI166 
EKB-569
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)
BAY 43-9006 / sorafenib
relaxin receptor RLX1
RLX2
RLX3
CD117 / c-KIT SCF CT53518 
PKC412 
SU11248 
imatinib mesylate / STI 571 (Gleevec / Glivec©)
BAY 43-9006 / sorafenib (Nexavar®; source :  Bayer AG and Onyx Pharmaceuticals Inc) (also an inihibitor of VEGFR2, c-KIT and RAF1ref)
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
    The FGF signaling pathway
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