STP : main TKCRs

MAIN TKCRs

Conserved sequences : a NTD Cys-rich region and a WSXWS motif.
The ligand induces dimerization of the TKCR, which in turn causes dimerization of the RCTK. The RCTK monomers undergo cross-phosphorylation : such activated RCTK can phosphorylate tyrosine residues on the TKCR (if the TKCR is multimeric, the b subunit only is phosphorylated). Suchb pY motifs on the TKCR recruit signaling molecules that are themselves phosphorylated by the TKCRs (IRSs, RTKs , STATs : phosphorylated STATs can create homodimers, heterodimers or heterotrimers. Different STATs have different specificities for different TKCRs)
Click here for their STP.

TKCR family TKCR name RCTKs expressed on .. ligand(s) antagonists agonists

interferon receptors IFNAR1 / IFN-aR / IFN-aRa / CD118 (multimeric) p130^Jak1
p135^Tyk2 IFN-a
IFN-b
IFN-k
IFN-w₁
IFN-t

IFNAR2 / IFN-aR2 / IFN-aRb_L (multimeric) p130^Jak1
p135^Tyk2 IFN-a
IFN-b
IFN-k
IFN-w₁
IFN-t

IL-28 and IL-29 R (multimeric : IL-28Ra + IL-10Rb) p130^Jak1 IL-28A / IFN-l₂
IL-28B / IFN-l₃
IL-29 / IFN-l₁

IFNGR1 / IFN-gR1 / IFN-gRa / CD119 (multimeric; IFN-g provides the NLS for nuclear transport of IFNGR-1 and STAT1a, which don't contain an intrinsic NLS.) p130^Jak1
p130^Jak2
p135^Tyk2 IFN-g

IFNGR2 (multimeric) p130^Jak1
p130^Jak2
p135^Tyk2 IFN-g

IL-10R (multimeric : CD210 / ILR10a + IL-10Rb) p130^Jak1
p135^Tyk2 IL-10

CD130 / gp130 IL-6R (multimeric : CD126 / IL-6Ra + CD130 / gp130 / IL-6Rb) p130^Jak1
p130^Jak2
p135^Tyk2 IL-6

IL-11R (multimeric : IL-11Ra + IL-11Rb + CD130 / gp130) p130^Jak1
p130^Jak2
p135^Tyk2 IL-11

IL-12R (multimeric : IL-12Rb1 / CD212 + IL-12Rb2) p130^Jak1
p130^Jak2
p135^Tyk2 IL-12

G-CSFR / CD114 p130^Jak1
p130^Jak2
p135^Tyk2
Syk
p53-56^Lyn G-CSF progenipoietin-4 (ProGP-4) (also for FLT-3 )

LIFR (multimeric : LIFR + CD130 / gp130) p130^Jak1
p130^Jak2
p135^Tyk2 LIF

CNTFR (multimeric : CD130 / gp130) p130^Jak2
p135^Tyk2 CNTF

OSMR (multimeric : OSMRb + CD130 / gp130) p130^Jak1
p130^Jak2
p135^Tyk2 induced in activated monocytes, constitutive in epithelial cells OsM
IL-31 (together with IL-31RA)

LEPR / OB-R Jak3 both AgRP /NPY - and a-MSH /CART -producing neurons of the arcuate nucleus; increases in the endometrium during the menstrual cycle secretory phase, decreases in subfertile women leptin leptin peptide antagonist (LPA2)

CD131 / gp140 / b_c IL-3R (multimeric : CD123 / IL-3Ra + CD131 / gp140 / b_c+ CD132 / g_c) p130^Jak1
p130^Jak2
p53-56^Lyn IL-3

IL-5R (multimeric : CDw125 / IL-5Ra + CD131 / gp140 / b_c) p130^Jak1
p130^Jak2 IL-5

GM-CSFR (multimeric : CD116 / c-fms / GMCSFRa + CD131 / gp140 / b_c) p130^Jak1
p130^Jak2 GM-CSF

CD132 / g_c IL-2R (multimeric : CD25 / IL-2Ra + CD122 / IL-2Rb + CD132 / g_c) p130^Jak1
Jak3
p56^Lck
p59^Fyn IL-7

IL-4R type I (multimeric : CD124 / IL-4Ra + CD132 / g_c) p130^Jak1
Jak3 mast cells , resting T and B cells, macrophages, myeloid progenitors, stromal cells, fibroblasts, and hepatocytes IL-4

IL-7R (multimeric : CD127 + CD132 / g_c) p130^Jak1
Jak3 IL-2

IL-9R (multimeric : IL-9Ra + CD132 / g_c p130^Jak1
Jak3
p135^Tyk2 IL-9

IL-13R (multimeric : CD213a1 / IL-13Ra₁ + CD213a2 / IL-13Ra₂ + CD132 / g_c + CD24 (?)) p130^Jak1
p130^Jak2
Jak3
p135^Tyk2 IL-13

IL-15R (multimeric : IL-15Ra + IL-15Rb + CD122 / IL-2Rb + CD132 / g_c) p130^Jak1
p130^Jak2
Jak3 IL-15

IL-21R (multimeric : IL-21R + CD132 / g_c) NK cells, T cells IL-21

IL-4R type II (multimeric : CD124 / IL-4Ra + CD213a1 / IL-13Ra₁) p130^Jak1
p130^Jak2
Jak3 B cells, macrophages, mast cells IL-4
IL-13 Y119D

IL-17R / CD217 IL-17

IL-17BR IL-17B
IL-17E

IL-19R IL-19

IL-20R (multimeric : IL-20Ra + IL-20Rb) IL-20

IL-22R subepithelial myofibroblasts (SEMFs)^ref IL-22

IL-23R (IL-23Ra + IL-12Rb1 / CD212) p130^Jak2
p135^Tyk2 IL-23

Iga / CD79a + Igb / CD79b Syk

CD3d e g + CD247 / z chain ZAP70 Ag

CD4 p56^Lck TcR
IL-16

CD8a or CD8b p56^Lck TcR

CD16a / FcgRIIIA or CD16b / FcgRIIIB p56^Lck

adipoR1 skeletal muscle, aortic endothelial cell^ref1,
ref2 (higher) proteolytic cleavage fragment oconsisting of the globular C-terminal domain of adiponectin (gAd) >> full-length adiponectin (fAd)^{ref1,
ref2,
ref3}

adipoR2 hepatocytes, aortic endothelial cell^ref1,
ref2 (lower) adiponectin (intemediate affinity for both gAd and fAd)^{ref1,
ref2,
ref3}

IL-31RA (together with OSMR) induced in activated monocytes, constitutive in epithelial cells IL-31

imidazol(in)e receptors (I-Rs). ["imidazoline," by consensus (International Union of Pharmacology), includes imidazole, imidazoline, and related compounds] imidazoline receptor 1 (I1R / I₁ / nischarin rostroventrolateral part of the brainstem, presynaptic (inhibit norepinephrine (NE) release from sympathetic nerve endings), lateral reticular nucleus, platelets , endocrine pancreas, heart, and kidney aganodine
4-chloro-2-(2-imidazolin-2-yl-amino)-isoindoline (BDF 6143)
1,3-di(2-tolyl)guanidine (DTG)
benazoline
clonidine (Catapres^®, Catapres TTS^®)
p-iodoclonidine (PIC)
cirazoline
cis-/trans-dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro
-3H-pyrrol-2-yl)-amine (LNP 509)
2-(2-chloro-4-iodo-phenylamino)-5-methyl-pyrroline (LNP 911)
4-chloro-2-(imidazolin-2-ylamino)-isoindoline (BDF 6143)
idazoxan
lofexidine (Britlofex^®)
moxonidine
rilmenidine
UK 14,304
imidazole-4-acetic acid-ribotide (IAA-RP)^ref imidazole-4-acetic acid (IAA)
efaroxan
SKF 86466

imidazoline receptor 2 (I2R / I₂) idazoxan

GH receptor family hCS / hPL and hGH receptor (GHR) / STH receptor

STP through d3-GHR (a dominant allele which lacks exon 3 for which 50% of Europeans are hetero- or homozygous) homo- or heterodimers is 30% higher than through full-length GHR homodimers^ref

p130^Jak2 hCS 1 / hPL
hCS 2
hGH / STH 1
hGH / STH 2 pegvisomant / B2036-PEG is a GH analogue that includes a single amino acid substitution at position 120 that generates the GHR antagonist. Additional changes include amino acid substitutions within binding site 1 and a further modification by the addition of polyethylene glycol moieties that increase the half-life and reduce the immunogenicity of the molecule.

EPOR p130^Jak1
p130^Jak2 all regions of kidney, mesangial, proximal and distal tubular cells, endometrial epithelial cells in the secretory > proliferative phase EPO
see erythropoiesis-stimulating agents (ESA)

PRL receptor p130^Jak2 PRL

THPO p130^Jak1
p135^Tyk2 mature platelets and megakaryocytes thrombopoietin
PEG-MGDF : a pegylated, truncated form of hTPO was effective but induced the production of neutralizing antiTPO antibodies, resulting in thrombocytopenia in some recipients. The agent was therefore withdrawn from further clinical investigation

AMG 531 (Amgen) (i.v./s.c.) consists of disulfide-bonded human IgG1 heavy-chain and kappa light-chain constant regions (an Fc fragment) with two identical peptide sequences linked covalently at residue 228 of the heavy chain with the use of a polyglycine. The Fc component extends the half-life of the molecule in the circulation. The peptide portion was selected by screening libraries of peptides that have no sequence homology with human thrombopoietin to find one with a tertiary structure that would allow it to bind to and activate the Mpl receptor. In healthy volunteers, AMG 531, a clear, colorless liquid administered by subcutaneous injection, increased platelet production and platelet counts and did not induce neutralizing or cross-reacting antibodies against TPO^{ref1,
ref2,
ref3}

eltrombopag (source : GlaxoSmith Kline) (p.o.)

Web resources :

Type I IFNs (a/b) pathway at STKE [free registration required !]
Type II IFNs (g) pathway at STKE [free registration required !]

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TKCR family	TKCR name	RCTKs	expressed on ..	ligand(s)	antagonists	agonists
interferon receptors	IFNAR1 / IFN-aR / IFN-aRa / CD118 (multimeric)	p130^Jak1 p135^Tyk2		IFN-a IFN-b IFN-k IFN-w₁ IFN-t
	IFNAR2 / IFN-aR2 / IFN-aRb_L (multimeric)	p130^Jak1 p135^Tyk2		IFN-a IFN-b IFN-k IFN-w₁ IFN-t
	IL-28 and IL-29 R (multimeric : IL-28Ra + IL-10Rb)	p130^Jak1		IL-28A / IFN-l₂ IL-28B / IFN-l₃ IL-29 / IFN-l₁
	IFNGR1 / IFN-gR1 / IFN-gRa / CD119 (multimeric; IFN-g provides the NLS for nuclear transport of IFNGR-1 and STAT1a, which don't contain an intrinsic NLS.)	p130^Jak1 p130^Jak2 p135^Tyk2		IFN-g
	IFNGR2 (multimeric)	p130^Jak1 p130^Jak2 p135^Tyk2		IFN-g
	IL-10R (multimeric : CD210 / ILR10a + IL-10Rb)	p130^Jak1 p135^Tyk2		IL-10
CD130 / gp130	IL-6R (multimeric : CD126 / IL-6Ra + CD130 / gp130 / IL-6Rb)	p130^Jak1 p130^Jak2 p135^Tyk2		IL-6
	IL-11R (multimeric : IL-11Ra + IL-11Rb + CD130 / gp130)	p130^Jak1 p130^Jak2 p135^Tyk2		IL-11
	IL-12R (multimeric : IL-12Rb1 / CD212 + IL-12Rb2)	p130^Jak1 p130^Jak2 p135^Tyk2		IL-12
	G-CSFR / CD114	p130^Jak1 p130^Jak2 p135^Tyk2 Syk p53-56^Lyn		G-CSF		progenipoietin-4 (ProGP-4) (also for FLT-3 )
	LIFR (multimeric : LIFR + CD130 / gp130)	p130^Jak1 p130^Jak2 p135^Tyk2		LIF
	CNTFR (multimeric : CD130 / gp130)	p130^Jak2 p135^Tyk2		CNTF
	OSMR (multimeric : OSMRb + CD130 / gp130)	p130^Jak1 p130^Jak2 p135^Tyk2	induced in activated monocytes, constitutive in epithelial cells	OsM IL-31 (together with IL-31RA)
	LEPR / OB-R	Jak3	both AgRP /NPY - and a-MSH /CART -producing neurons of the arcuate nucleus; increases in the endometrium during the menstrual cycle secretory phase, decreases in subfertile women	leptin	leptin peptide antagonist (LPA2)
CD131 / gp140 / b_c	IL-3R (multimeric : CD123 / IL-3Ra + CD131 / gp140 / b_c+ CD132 / g_c)	p130^Jak1 p130^Jak2 p53-56^Lyn		IL-3
	IL-5R (multimeric : CDw125 / IL-5Ra + CD131 / gp140 / b_c)	p130^Jak1 p130^Jak2		IL-5
	GM-CSFR (multimeric : CD116 / c-fms / GMCSFRa + CD131 / gp140 / b_c)	p130^Jak1 p130^Jak2		GM-CSF
CD132 / g_c	IL-2R (multimeric : CD25 / IL-2Ra + CD122 / IL-2Rb + CD132 / g_c)	p130^Jak1 Jak3 p56^Lck p59^Fyn		IL-7
	IL-4R type I (multimeric : CD124 / IL-4Ra + CD132 / g_c)	p130^Jak1 Jak3	mast cells , resting T and B cells, macrophages, myeloid progenitors, stromal cells, fibroblasts, and hepatocytes	IL-4
	IL-7R (multimeric : CD127 + CD132 / g_c)	p130^Jak1 Jak3		IL-2
	IL-9R (multimeric : IL-9Ra + CD132 / g_c	p130^Jak1 Jak3 p135^Tyk2		IL-9
	IL-13R (multimeric : CD213a1 / IL-13Ra₁ + CD213a2 / IL-13Ra₂ + CD132 / g_c + CD24 (?))	p130^Jak1 p130^Jak2 Jak3 p135^Tyk2		IL-13
	IL-15R (multimeric : IL-15Ra + IL-15Rb + CD122 / IL-2Rb + CD132 / g_c)	p130^Jak1 p130^Jak2 Jak3		IL-15
	IL-21R (multimeric : IL-21R + CD132 / g_c)		NK cells, T cells	IL-21
	IL-4R type II (multimeric : CD124 / IL-4Ra + CD213a1 / IL-13Ra₁)	p130^Jak1 p130^Jak2 Jak3	B cells, macrophages, mast cells	IL-4 IL-13		Y119D
	IL-17R / CD217			IL-17
	IL-17BR			IL-17B IL-17E
	IL-19R			IL-19
	IL-20R (multimeric : IL-20Ra + IL-20Rb)			IL-20
	IL-22R		subepithelial myofibroblasts (SEMFs)^ref	IL-22
	IL-23R (IL-23Ra + IL-12Rb1 / CD212)	p130^Jak2 p135^Tyk2		IL-23
	Iga / CD79a + Igb / CD79b	Syk
	CD3d e g + CD247 / z chain	ZAP70		Ag
	CD4	p56^Lck		TcR IL-16
	CD8a or CD8b	p56^Lck		TcR
	CD16a / FcgRIIIA or CD16b / FcgRIIIB	p56^Lck
	adipoR1		skeletal muscle, aortic endothelial cell^ref1, ref2 (higher)	proteolytic cleavage fragment oconsisting of the globular C-terminal domain of adiponectin (gAd) >> full-length adiponectin (fAd)^{ref1, ref2, ref3}
	adipoR2		hepatocytes, aortic endothelial cell^ref1, ref2 (lower)	adiponectin (intemediate affinity for both gAd and fAd)^{ref1, ref2, ref3}
	IL-31RA (together with OSMR)		induced in activated monocytes, constitutive in epithelial cells	IL-31
imidazol(in)e receptors (I-Rs). ["imidazoline," by consensus (International Union of Pharmacology), includes imidazole, imidazoline, and related compounds]	imidazoline receptor 1 (I1R / I₁ / nischarin		rostroventrolateral part of the brainstem, presynaptic (inhibit norepinephrine (NE) release from sympathetic nerve endings), lateral reticular nucleus, platelets , endocrine pancreas, heart, and kidney		aganodine 4-chloro-2-(2-imidazolin-2-yl-amino)-isoindoline (BDF 6143) 1,3-di(2-tolyl)guanidine (DTG) benazoline clonidine (Catapres^®, Catapres TTS^®) p-iodoclonidine (PIC) cirazoline cis-/trans-dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro -3H-pyrrol-2-yl)-amine (LNP 509) 2-(2-chloro-4-iodo-phenylamino)-5-methyl-pyrroline (LNP 911) 4-chloro-2-(imidazolin-2-ylamino)-isoindoline (BDF 6143) idazoxan lofexidine (Britlofex^®) moxonidine rilmenidine UK 14,304 imidazole-4-acetic acid-ribotide (IAA-RP)^ref	imidazole-4-acetic acid (IAA) efaroxan SKF 86466
	imidazoline receptor 2 (I2R / I₂)				idazoxan
GH receptor family	hCS / hPL and hGH receptor (GHR) / STH receptor STP through d3-GHR (a dominant allele which lacks exon 3 for which 50% of Europeans are hetero- or homozygous) homo- or heterodimers is 30% higher than through full-length GHR homodimers^ref	p130^Jak2		hCS 1 / hPL hCS 2 hGH / STH 1 hGH / STH 2	pegvisomant / B2036-PEG is a GH analogue that includes a single amino acid substitution at position 120 that generates the GHR antagonist. Additional changes include amino acid substitutions within binding site 1 and a further modification by the addition of polyethylene glycol moieties that increase the half-life and reduce the immunogenicity of the molecule.
	EPOR	p130^Jak1 p130^Jak2	all regions of kidney, mesangial, proximal and distal tubular cells, endometrial epithelial cells in the secretory > proliferative phase	EPO		see erythropoiesis-stimulating agents (ESA)
	PRL receptor	p130^Jak2		PRL
	THPO	p130^Jak1 p135^Tyk2	mature platelets and megakaryocytes	thrombopoietin		PEG-MGDF : a pegylated, truncated form of hTPO was effective but induced the production of neutralizing antiTPO antibodies, resulting in thrombocytopenia in some recipients. The agent was therefore withdrawn from further clinical investigation AMG 531 (Amgen) (i.v./s.c.) consists of disulfide-bonded human IgG1 heavy-chain and kappa light-chain constant regions (an Fc fragment) with two identical peptide sequences linked covalently at residue 228 of the heavy chain with the use of a polyglycine. The Fc component extends the half-life of the molecule in the circulation. The peptide portion was selected by screening libraries of peptides that have no sequence homology with human thrombopoietin to find one with a tertiary structure that would allow it to bind to and activate the Mpl receptor. In healthy volunteers, AMG 531, a clear, colorless liquid administered by subcutaneous injection, increased platelet production and platelet counts and did not induce neutralizing or cross-reacting antibodies against TPO^{ref1, ref2, ref3} eltrombopag (source : GlaxoSmith Kline) (p.o.)