R-SMAD

(Redirected from Receptor regulated SMAD) Receptor regulated SMAD proteins

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R-SMADs are receptor-regulated SMADs. SMADs are transcription factors that transduce extracellular TGF-β superfamily ligand signaling from cell membrane bound TGF-β receptors into the nucleus where they activate transcription TGF-β target genes. R-SMADS are directly phosphorylated on their c-terminus by type 1 TGF-β receptors through their intracellular kinase domain, leading to R-SMAD activation.

R-SMADS include SMAD2 and SMAD3 from the TGF-β/Activin/Nodal branch, and SMAD1, SMAD5 and SMAD9 from the BMP/GDP branch of TGF-β signaling.

In response to signals by the TGF-β superfamily of ligands these proteins associate with receptor kinases and are phosphorylated at an SSXS motif at their extreme C-terminus. These proteins then typically bind to the common mediator Smad or co-SMAD SMAD4.

Smad complexes then accumulate in the cell nucleus where they regulate transcription of specific target genes:

SMAD2 and SMAD3 are activated in response to TGF-β/Activin or Nodal signals.
SMAD1, SMAD5 and SMAD9 (also known as SMAD8) are activated in response to BMPs bone morphogenetic protein or GDP signals.

SMAD6 and SMAD7 may be referred to as I-SMADs (inhibitory SMADS), which form trimers with R-SMADS and block their ability to induce gene transcription by competing with R-SMADs for receptor binding and by marking TGF-β receptors for degradation.

References

^ Wharton K, Derynck R (November 2009). "TGFbeta family signaling: novel insights in development and disease". Development. 136 (22): 3691–7. doi:10.1242/dev.040584. PMID 19855012.

External links

R-Smad+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

Transcription factors and intracellular receptors

(1) Basic domains

(1.1) Basic leucine zipper (bZIP)

Activating transcription factor
- AATF
- 1
- 2
- 3
- 4
- 5
- 6
- 7
AP-1
- c-Fos
- FOSB
- FOSL1
- FOSL2
- JDP2
- c-Jun
- JUNB
- JunD
BACH
- 1
- 2
BATF
BLZF1
C/EBP
- α
- β
- γ
- δ
- ε
- ζ
CREB
- 1
- 3
- L1
CREM
DBP
DDIT3
GABPA
GCN4
HLF
MAF
- B
- F
- G
- K
NFE
- 2
- L1
- L2
- L3
NFIL3
NRL
NRF
- 1
- 2
- 3
XBP1

(1.2) Basic helix-loop-helix (bHLH)

Group A	AS-C ASCL1 ASCL2 ATOH1 HAND 1 2 MESP2 Myogenic regulatory factors MyoD Myogenin MYF5 MYF6 NeuroD 1 2 Neurogenins 1 2 3 OLIG 1 2 Paraxis TCF15 Scleraxis SLC LYL1 TAL 1 2 Twist
Group B	FIGLA Myc c-Myc l-Myc n-Myc MXD4 TCF4
Group C bHLH-PAS	AhR AHRR ARNT ARNTL ARNTL2 CLOCK HIF 1A EPAS1 3A NPAS 1 2 3 PER 1 2 3 Period SIM 1 2
Group D	BHLH 2 3 9 Pho4 ID 1 2 3 4
Group E	HES 1 2 3 4 5 6 7 HEY 1 2 L
Group F bHLH-COE	EBF1

(1.3) bHLH-ZIP

(1.4) NF-1

NFI
- A
- B
- C
- X
SMAD
- R-SMAD
  - 1
  - 2
  - 3
  - 5
  - 9
- I-SMAD
  - 6
  - 7
- 4)

(1.5) RF-X

RFX
- 1
- 2
- 3
- 4
- 5
- 6
- ANK

(1.6) Basic helix-span-helix (bHSH)

AP-2
- α
- β
- γ
- δ
- ε

(2) Zinc finger DNA-binding domains

(2.1) Nuclear receptor (Cys₄)

subfamily 1	Thyroid hormone α β CAR FXR LXR α β PPAR α β/δ γ PXR RAR α β γ ROR α β γ Rev-ErbA α β VDR
subfamily 2	COUP-TF (I II Ear-2 HNF4 α γ PNR RXR α β γ Testicular receptor 2 4 TLX
subfamily 3	Steroid hormone Androgen Estrogen α β Glucocorticoid Mineralocorticoid Progesterone Estrogen related α β γ
subfamily 4	NUR NGFIB NOR1 NURR1
subfamily 5	LRH-1 SF1
subfamily 6	GCNF
subfamily 0	DAX1 SHP

(2.2) Other Cys₄

GATA
- 1
- 2
- 3
- 4
- 5
- 6
MTA
- 1
- 2
- 3
TRPS1

(2.3) Cys₂His₂

General transcription factors
- TFIIA
- TFIIB
- TFIID
- TFIIE
  - 1
  - 2
- TFIIF
- 1
- 2
  - TFIIH
  - 1
  - 2
  - 4
  - 2I
  - 3A
  - 3C1
  - 3C2

ATBF1
BCL
- 6
- 11A
- 11B
CTCF
E4F1
EGR
- 1
- 2
- 3
- 4
ERV3
GFI1
GLI family
- 1
- 2
- 3
- REST
- S1
- S2
- YY1
HIC
- 1
- 2
HIVEP
- 1
- 2
- 3
IKZF
- 1
- 2
- 3
ILF
- 2
- 3
Sp/KLF family
- KLF
  - 1
  - 2
  - 3
  - 4
  - 5
  - 6
  - 7
  - 8
  - 9
  - 10
  - 11
  - 12
  - 13
  - 14
  - 15
  - 17
- SP
  - 1
  - 2
  - 4
  - 7
  - 8
MTF1
MYT1
OSR1
PRDM9
SALL
- 1
- 2
- 3
- 4
TSHZ3
WT1
Zbtb7
- 7A
- 7B
ZBTB
- 11
- 16
- 17
- 20
- 21
- 32
- 33
- 40
zinc finger
- 3
- 7
- 9
- 10
- 19
- 22
- 24
- 33B
- 34
- 35
- 41
- 43
- 44
- 51
- 74
- 143
- 146
- 148
- 165
- 202
- 217
- 219
- 238
- 239
- 259
- 267
- 268
- 281
- 300
- 318
- 330
- 346
- 350
- 365
- 366
- 384
- 423
- 451
- 452
- 471
- 593
- 638
- 644
- 649
- 655
- 804A

(2.4) Cys₆

HIVEP1

(2.5) Alternating composition

AIRE
DIDO1
GRLF1
ING
- 1
- 2
- 4
JARID
- 1A
- 1B
- 1C
- 1D
- 2
JMJD1B

(2.6) WRKY

WRKY

(3) Helix-turn-helix domains

(3.1) Homeodomain

Antennapedia
ANTP class

protoHOX Hox-like	ParaHox Gsx 1 2 Xlox PDX1 Cdx 1 2 4 extended Hox: Evx1 Evx2 MEOX1 MEOX2 Homeobox A1 A2 A3 A4 A5 A7 A9 A10 A11 A13 B1 B2 B3 B4 B5 B6 B7 B8 B9 B13 C4 C5 C6 C8 C9 C10 C11 C12 C13 D1 D3 D4 D8 D9 D10 D11 D12 D13 GBX1 GBX2 MNX1
metaHOX NK-like	BARHL1 BARHL2 BARX1 BARX2 BSX DBX 1 2 DLX 1 2 3 4 5 6 EMX 1 2 EN 1 2 HHEX HLX LBX1 LBX2 MSX 1 2 NANOG NKX 2-1 2-2 2-3 2-5 3-1 3-2 HMX1 HMX2 HMX3 6-1 6-2 NOTO TLX1 TLX2 TLX3 VAX1 VAX2

other

ARX
CRX
CUTL1
FHL
- 1
- 2
- 3
HESX1
HOPX
LMX
- 1A
- 1B
NOBOX
TALE
- IRX
  - 1
  - 2
  - 3
  - 4
  - 5
  - 6
  - MKX
- MEIS
  - 1
  - 2
- PBX
  - 1
  - 2
  - 3
- PKNOX
  - 1
  - 2
- SIX
  - 1
  - 2
  - 3
  - 4
  - 5
PHF
- 1
- 3
- 6
- 8
- 10
- 16
- 17
- 20
- 21A
POU domain
- PIT-1
- BRN-3: A
- B
- C
- Octamer transcription factor: 1
- 2
- 3/4
- 6
- 7
- 11
SATB2
ZEB
- 1
- 2

(3.2) Paired box

PAX
- 1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 9
PRRX
- 1
- 2
PROP1
PHOX
- 2A
- 2B
RAX
SHOX
SHOX2
VSX1
VSX2
Bicoid
- GSC
- BICD2
- OTX
  - 1
  - 2
- PITX
  - 1
  - 2
  - 3

(3.3) Fork head / winged helix

E2F
- 1
- 2
- 3
- 4
- 5
FOX proteins
- A1
- A2
- A3
- B1
- B2
- C1
- C2
- D1
- D2
- D3
- D4
- D4L1
- D4L3
- D4L4
- D4L5
- D4L6
- E1
- E3
- F1
- F2
- G1
- H1
- I1
- I2
- I3
- J1
- J2
- J3
- K1
- K2
- L1
- L2
- M1
- N1
- N2
- N3
- N4
- O1
- O3
- O4
- O6
- P1
- P2
- P3
- P4
- Q1
- R1
- R2
- S1

(3.4) Heat shock factors

HSF
- 1
- 2
- 4

(3.5) Tryptophan clusters

ELF
- 2
- 4
- 5
EHF
ELK
- 1
- 3
- 4
ERF
ETS
- 1
- 2
- ERG
- SPIB
ETV
- 1
- 4
- 5
- 6
FLI1
Interferon regulatory factors
- 1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
MYB
MYBL2

(3.6) TEA domain

transcriptional enhancer factor
- 1
- 2
- 3
- 4

(4) β-Scaffold factors with minor groove contacts

(4.1) Rel homology region	NF-κB NFKB1 NFKB2 REL RELA RELB NFAT C1 C2 C3 C4 5
(4.2) STAT	STAT 1 2 3 4 5 6
(4.3) p53-like	p53 p63 p73 family p53 TP63 p73 TBX 1 2 3 5 19 21 22 TBR1 TBR2 TFT MYRF
(4.4) MADS box	Mef2 A B C D SRF
(4.6) TATA-binding proteins	TBP TBPL1
(4.7) High-mobility group	BBX HMGB 1 2 3 4 HMGN 1 2 3 4 HNF 1A 1B SOX 1 2 3 4 5 6 8 9 10 11 12 13 14 15 17 18 21 SRY SSRP1 TCF/LEF TCF 1 3 4 LEF1 TOX 1 2 3 4
(4.9) Grainyhead	TFCP2
(4.10) Cold-shock domain	CSDA YBX1
(4.11) Runt	CBF CBFA2T2 CBFA2T3 RUNX1 RUNX2 RUNX3 RUNX1T1

(0) Other transcription factors

(0.2) HMGI(Y)	HMGA 1 2 HBP1
(0.3) Pocket domain	Rb RBL1 RBL2
(0.5) AP-2/EREBP-related factors	Apetala 2 EREBP B3
(0.6) Miscellaneous	ARID 1A 1B 2 3A 3B 4A CAP IFI 16 35 MLL 2 3 T1 MNDA NFY A B C Rho/Sigma

see also transcription factor/coregulator deficiencies

Cell signaling: TGFβ signaling pathway

TGF beta superfamily of ligands

Ligand of ACVR or TGFBR	TGF beta family TGF-β1 TGF-β2 TGF-β3 Activin and inhibin INHA INHBA INHBB INHBC Nodal
Ligand of BMPR	Bone morphogenetic proteins BMP2 BMP3 BMP4 BMP5 BMP6 BMP7 BMP8a BMP8b BMP10 BMP15 Growth differentiation factors GDF1 GDF2 GDF3 GDF5 GDF6 GDF7 Myostatin/GDF8 GDF9 GDF10 GDF11 GDF15 Anti-müllerian hormone

TGF beta receptors
(Activin, BMP, family)

TGFBR1:	Activin type 1 receptors ACVR1 ACVR1B ACVR1C ACVRL1 BMPR1 BMPR1A BMPR1B
TGFBR2:	Activin type 2 receptors ACVR2A ACVR2B AMHR2 BMPR2
TGFBR3:	betaglycan

Transducers/SMAD

Ligand inhibitors

Coreceptors

BAMBI
Cripto

Other

SARA

TGFβ receptor superfamily modulators

Type I

ALK1 (ACVRL1)	Agonists: Activin (A, B, AB) Avotermin BMP (10) Cetermin GDF (2 (BMP9)) TGFβ (1, 2, 3) Antibodies: Ascrinvacumab Kinase inhibitors: K-02288 ML-347 (LDN-193719, VU0469381) Decoy receptors: Dalantercept Other inhibitors: Disitertide
ALK2 (ACVR1A)	Agonists: Activin (A, B, AB) AMH (MIS) Avotermin BMP (5, 6, 7, 8A, 8B) Eptotermin alfa TGFβ (1, 2, 3) Kinase inhibitors: DMH-1 DMH-2 Dorsomorphin (BML-275) K-02288 ML-347 (LDN-193719, VU0469381)
ALK3 (BMPR1A)	Agonists: AMH (MIS) BMP (2, 4, 5, 6, 7, 8A, 8B) Dibotermin alfa Eptotermin alfa Kinase inhibitors: DMH-2 Dorsomorphin (BML-275) K-02288
ALK4 (ACVR1B)	Agonists: Activin (A, B, AB) GDF (1, 3, 11 (BMP11)) Myostatin (GDF8) Nodal Antagonists: Inhibin (A, B) Lefty (1, 2) Kinase inhibitors: A 83-01 SB-431542 SB-505124
ALK5 (TGFβR1)	Agonists: Avotermin GDF (10 (BMP3B), 11 (BMP11)) TGFβ (1, 2, 3) Antibodies: Fresolimumab Lerdelimumab Metelimumab Kinase inhibitors: A 83-01 D-4476 GW-788388 LY-364947 LY-2109761 Galunisertib (LY-2157299) R-268712 RepSox (E-616452, SJN-2511) SB-431542 SB-505124 SB-525334 SD-208
ALK6 (BMPR1B)	Agonists: BMP (2, 4, 5, 6, 7, 8A, 8B, 15 (GDF9B)) Dibotermin alfa Eptotermin alfa GDF (5 (BMP14), 6 (BMP13), 7 (BMP12), 9, 15) Radotermin Kinase inhibitors: DMH-2 Dorsomorphin (BML-275) K-02288
ALK7 (ACVR1C)	Agonists: GDF (1, 3, 11 (BMP11)) Nodal Antagonists: Lefty (1, 2) Kinase inhibitors: A 83-01 SB-431542 SB-505124

Type II

TGFβR2	Agonists: Avotermin GDF (10 (BMP3B)) TGFβ (1, 2, 3) Antibodies: Fresolimumab Lerdelimumab Metelimumab Kinase inhibitors: DMH-2 LY-364947
BMPR2	Agonists: BMP (2, 4, 6, 7, 10) Dibotermin alfa Eptotermin alfa GDF (2 (BMP9), 5 (BMP14), 6 (BMP13), 7 (BMP12)) Radotermin Antagonists: Inhibin (A, B)
ACVR2A (ACVR2)	Agonists: Activin (A, B, AB) BMP (2, 4, 5, 6, 7, 8A, 8B, 15 (GDF9B)) Dibotermin alfa Eptotermin alfa GDF (1, 3, 5 (BMP14), 6 (BMP13), 7 (BMP12), 9, 11 (BMP11), 15) Myostatin (GDF8) Nodal Radotermin Antagonists: Inhibin (A, B) Lefty (1, 2) Decoy receptors: Sotatercept
ACVR2B	Agonists: Activin (A, B, AB) BMP (2, 4, 6, 7) Dibotermin alfa Eptotermin alfa GDF (1, 3, 5 (BMP14), 6 (BMP13), 7 (BMP12)) Myostatin (GDF8) Nodal Osteogenin (BMP3, BMP3A) Radotermin Antagonists: Inhibin (A, B) Lefty (1, 2) Decoy receptors: Ramatercept
AMHR2 (AMHR)	Agonists: AMH (MIS)

Type III

TGFβR3 (β-glycan)	Ligands: Avotermin Inhibin (A, B) TGFβ (1, 2, 3)

Unsorted

Endogenous antagonists/inhibitors: BAMBI
Cerberus (CER1)
Chordin
DAN (PARN)
Decorin
Follistatin
Gremlin (Drm)
LTBP1
Noggin
TGIF
Thrombospondin 1 (THBS1)
Tomoregulin 1

Antibodies: Stamulumab (against myostatin)
TRC105 (against endoglin)

Others: Endoglin

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