STP : main RTKs

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 :

quercetin (it is also an antioxidant and an inhibitor of protein serine/threonine kinases )
genistein
herbimycin A
geldanamycin
lavendustin A
tyrphostins (synthetic derivatives of erbstatin )

AG126
AG213
AG370
AG490
RG50862
RG50864

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 :

growth
differentiation
apoptosis
inflammation

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 kinase^ref : 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-A_{121, 165, 189 or 206} PlGF VEGF-B		SU11248 PTK787/ZK222584 (PTK/ZK) AZD2171 (Recentin^®; source : AstraZeneca)
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 RAF1 ^ref) imidazoacridinones C-1311 (Symadex^®; source : Xanthus Pharmaceuticals, Inc.)
FLK-1 / VEGFR2 / KDR			VEGF-A_{121, 165, 189 or 206} VEGF-C VEGF-D VEGF-E		PTK787/ZK222584 (PTK/ZK) ZD6474 AZD2171, orally bioavailable^ref BAY 43-9006 / sorafenib (Nexavar^®; source : Bayer AG and Onyx Pharmaceuticals Inc) (also an inihibitor of VEGFR2, c-KIT and RAF1 ^ref) YM-359445, an orally bioavailable^ref
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 / EGF105084 (Tykerb^©; source : GSK) 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 RAF1 ^ref)
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 : BDNF GDNF NGF ...
	TrkB	pre- and postsynaptic neurons of excitatory synaptic transmission in the CA1 region of the hippocampus	neurotrophins / neurotrophic factors : BDNF NTF-3 ...
	TrkC		neurotrophins / neurotrophic factors : NTF-3 ...
	TrkE / discoidin domain receptor family, member 1
p75^NTR			neurotrophins / neurotrophic factors : BDNF GDNF NGF ...
RET		nociceptors	neurotrophins / neurotrophic factors : artemin (uses GPI-linked GDNF family receptor (GFR)-a₃ as a coreceptor)
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 disorders^ref

The FGF signaling pathway

Web resources :

The International Receptor Tyrosine Kinase (RTK) Networks Consortium

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