TGFB1:TGFBR1:TGFBR2

Complex TGFB1:TGFBR1:TGFBR2 map


Complex composition:

  1. TGFB1 map
  2. TGFBR1 map
  3. TGFBR2 map




TGFB1|​hm2:​TGFBR1|​Ser_pho|​hm2:​TGFBR2|​Ser_pho|​hm2@Cytoplasm

Identifiers
NAME:TGFB1:TGFBR1:TGFBR2

Maps_Modules
 EMT  map  / EMT_REGULATORS  map

References
Reference_bigin:
PMID:22943793
TGFb binds to homodimer TGFBR2 first
TGFBR2 phosphorylates the GS domain of homodimeric TFGBR1 on serine residues
This phosphorylation leads to incorporation of TGFBR1 and formation of a large ligand-receptor complex of fimeric TGFB and two pairs of TGFBR1 and TGFBR2
PMID:12809600
PMID:22710166
The active ligand–receptor complex is a heterotetrameric complex
This complex consists of an active dimer of TGFB and homodimers of both TGFBRI and TGFBR2.
Within the active receptor complex, TGFBR2autophosphorylates itself and catalyzes transphosphorylation of the TGFBR1.
Transphosphorylation of the TGFBRI activates its kinase activity.
Reference_end
e_re122( EMT  map ):
e_re249( EMT  map ):
PMID:9865696
SARA interacts directly with Smad2 and Smad3
The C-ter of SARA interacts TGFBR1 and TGFBR2
SARA presents Smad2 to the TGFb receptor
Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2-Smad4 complexes and nuclear translocation.
PMID:12154066
Small GTPases such as Rab5 catalyse movement of activated receptor complexes to early endosomal compartments
Here, the complex encounter SARA: a phospholipid-bound carrier
SARA presents Smads to the TGFBR1
PMID:11013220
The ligand bound activated receptor complex is internalized via endocytosis
PMID:19050695
2 pathways of receptor complex endocytosis: clathrin-mediated or caveolae-mediated
Through the clathrin pathway, activated ligan-receptor complex are brought into early endosomes which are enriched with scaffold proteins such as SARA.
PMID:12717440
PMID:12724770
Clathrin-dependent internalization into endosome, where the Smad2 anchor SARA is enriched, promotes TGFB signalling.
Raft-caveolar internalization pathway contains the Smad7-Smurf2 bound receptor and is required for rapid receptor turnover.
Thus, segregation of TGF-b receptors into distinct endocytic compartments regulates Smad activation and receptor turnover
e_re1272( EMT  map ):
PMID:17673906
Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 on tyrosine and serine.
TGFB-induced SHC1 phosphorylation induces SHC1 association with Grb2 and Sos
PMID:12767520
Upon IGF stimulation, the activated IGF1R recruits and directly phosphorylates SHC1, leading to cellular proliferation
e_re1359( EMT  map ):
PMID:18758450
The ubiquitin ligase (E3) TRAF6 interacts with a consensus motif present in TGFBR1.
The TGFBR1–TRAF6 interaction is required for TGFB-induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1–p38/JNK pathway
TGFB specifically activates TAK1 (MAP3K7) through interaction of TGFBRI with TRAF6.
The kinase activity of TGFBRI is not required for activation of TAK1 and p38.
Model in which TGFB – induced activation of TAK1 is initiated by ligand-induced oligomerization of TGFBreceptors. This in turn cause dimerization of TRAF6, followed by auto-ubiquitylation and activation.
This possibility is consistent with the observation that artifical dimerization of TRAF6 causes its auto-ubiquitylation.
Activated TRAF6 then causes Lys 63-linked ubiquitylation and activation of TAK1 (MAP3K7). TAK1 may be further activated by juxtaposition-induced autophosphorylation.
The recruitment of TAK1 may be facilitated by Smad7, which has been shown to have an adaptor function in the pathway
PMID:18922473
TRAF6 is specifically required for the Smad-independent activation of JNK and p38.
The carboxyl TRAF homology domain physically interacts with TGFB receptors.
TGFB induces K63-linked ubiquitination of TRAF6 and promotes association between TRAF6 and TAK1 (MAP3K7).
TGFB activates JNK and p38 through a mechanism similar to that operating in the interleukin1B/Toll- like receptor pathway.

Confidence
REF=5 FUNC=5

TGFB1|​hm2:​TGFBR1|​hm2:​TGFBR2|​hm2@Cytoplasm

Identifiers
NAME:TGFB1:TGFBR1:TGFBR2

Maps_Modules
 EMT  map  / EMT_REGULATORS  map

References
Reference_bigin:
PMID:22943793
TGFb binds to homodimer TGFBR2 first
TGFBR2 phosphorylates the GS domain of homodimeric TFGBR1 on serine residues
This phosphorylation leads to incorporation of TGFBR1 and formation of a large ligand-receptor complex of fimeric TGFB and two pairs of TGFBR1 and TGFBR2
PMID:12809600
PMID:22710166
The active ligand–receptor complex is a heterotetrameric complex
This complex consists of an active dimer of TGFB and homodimers of both TGFBRI and TGFBR2.
Within the active receptor complex, TGFBR2autophosphorylates itself and catalyzes transphosphorylation of the TGFBR1.
Transphosphorylation of the TGFBRI activates its kinase activity.
Reference_end
e_re122( EMT  map ):
e_re342( EMT  map ):
PMID:15761153
Occludin is a structural component of tight junctions that is associated with the cell polarity network.
Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT
Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB
but its association with the TGFBR2 increased in a TGFB-dependent manner
PMID:15761148
TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin
After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1.

Confidence
REF=2 FUNC=5


Modifications:
Participates in complexes:
In compartment: Cytoplasm
  1. TGFB1|​hm2:​TGFBR1|​hm2:​TGFBR2|​hm2@Cytoplasm map

  2. TGFB1|​hm2:​TGFBR1|​Ser_pho|​hm2:​TGFBR2|​Ser_pho|​hm2@Cytoplasm map

Participates in reactions:
As Reactant or Product:

  1. TGFB1|​hm2:​TGFBR1|​Ser_pho|​hm2:​TGFBR2|​Ser_pho|​hm2@Cytoplasm map map TGFB1|​hm2:​TGFBR1|​hm2:​TGFBR2|​hm2@Cytoplasm map

  2. TGFB1|​hm2:​TGFBR1|​hm2:​TGFBR2|​hm2@Cytoplasm map + ATP@Extracellular space map map TGFB1|​hm2:​TGFBR1|​Ser_pho|​hm2:​TGFBR2|​Ser_pho|​hm2@Cytoplasm map + ADP@Extracellular space map
  3. TGFB1|​hm2:​TGFBR2|​hm2@Cytoplasm map + TGFBR1|​hm2@Cytoplasm map map TGFB1|​hm2:​TGFBR1|​hm2:​TGFBR2|​hm2@Cytoplasm map
  4. SARA*@Early Endosome map + TGFB1|​hm2:​TGFBR1|​Ser_pho|​hm2:​TGFBR2|​Ser_pho|​hm2@Cytoplasm map map SARA*:​TGFB1|​hm2:​TGFBR1|​Ser_pho|​hm2:​TGFBR2|​Ser_pho|​hm2@Early Endosome map
  5. Occludin*:​PARD6A:​TGFBR1|​hm2@Cytoplasm map + TGFB1|​hm2:​TGFBR1|​hm2:​TGFBR2|​hm2@Cytoplasm map map Occludin*:​PARD6A:​TGFB1|​hm2:​TGFBR1|​hm2:​TGFBR2|​hm2@Cytoplasm map

As Catalyser:

  1. TGFB1|​hm2:​TGFBR1|​hm2:​TGFBR2|​hm2@Cytoplasm map + ATP@Extracellular space map map TGFB1|​hm2:​TGFBR1|​Ser_pho|​hm2:​TGFBR2|​Ser_pho|​hm2@Cytoplasm map + ADP@Extracellular space map

  2. SHC1_p66_p52*@Cytoplasm map map SHC1_p66_p52*|​Y_pho|​S_pho|​active@Cytoplasm map
  3. TRAF6@Cytoplasm map map TRAF6|​ubi|​hm2|​active@Cytoplasm map

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