SARA*

Protein SARA* map

Identifiers
zinc finger, FYVE domain containing 9
HUGO:ZFYVE9 HGNC:6775 ENTREZ:9372 UNIPROT:O95405 GENECARDS:ZFYVE9 REACTOME:58931 KEGG:9372 ATLASONC:GC_ZFYVE9 WIKI:ZFYVE9

Maps_Modules
 EMT  map  / EMT_REGULATORS  map

References
PMID:9865696
SARA interacts directly with Smad2 and Smad3
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:11792802
-SARA contains a FYVE motif which is known to bind phosphatidylinositol 3-phosphate.
It might anchor Smad2 to the inner leaflet of the plasma membrane or endosomal vesicles.
SARA thus provides a first example of how TGFB signaling centres may be organised at the plasma membrane or endosomal vesicles.
-Several other proteins with possible roles in Smad anchoring:
PMID:10678166
Microtubules can anchor inactive Smads in the cytoplasm
Activation by a ligand results in dissociation of the Smads from the microtubule network
It is possible that microtubules serve as tracks for intracellular Smad movement
PMID:11278410
Filamin, an actin crosslinking factor and scaffolding protein also associates with Smads and positively regulates transduction of Smad signals.

SARA*@Early Endosome

Maps_Modules
 EMT  map  / EMT_REGULATORS  map

References
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
e_re218( EMT  map ):
Phosphorylation of Smad2 induces dissociation from SARA
with concomitant formation of Smad2/ Smad4 complexes
and nuclear translocation.
e_re216( EMT  map ):
PMID:11792802
SARA is a cytoplasmic protein that specifically interacts withe no-activated Smad2 and the receptor complex
SARA thus forms the bridge between the receptor and Smad2 and assisting in the specific phosphorylation of Smad2 by the TGFBR1
The stable interaction of SARA with non-phosphorylated Smad2 also inhibits nuclear import of Smad2
PMID:10934479
The nuclear import function of Smad2 is masked by SARA and unmasked by TGFB- dependent phosphorylation
e_re249( EMT  map ):
PMID:22710166
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


Modifications:
In compartment: Early Endosome
  1. SARA*@Early Endosome map

Participates in complexes:
In compartment: Early Endosome

  1. SARA*:​SMAD2@Early Endosome map

  2. SARA*:​SMAD3@Early Endosome map
  3. SARA*:​SMAD2|​S467_pho|​S465_pho@Early Endosome map
  4. SARA*:​SMAD3|​S423_pho|​S425_pho@Early Endosome map
  5. SARA*:​TGFB1|​hm2:​TGFBR1|​Ser_pho|​hm2:​TGFBR2|​Ser_pho|​hm2@Early Endosome map

Participates in reactions:
As Reactant or Product:

  1. SMAD2@Cytoplasm map + SARA*@Early Endosome map map SARA*:​SMAD2@Early Endosome map

  2. SARA*:​SMAD2@Early Endosome map + ATP@Cytoplasm map map SARA*:​SMAD2|​S467_pho|​S465_pho@Early Endosome map + ADP@Cytoplasm map
  3. SARA*:​SMAD2|​S467_pho|​S465_pho@Early Endosome map map SMAD2|​S467_pho|​S465_pho@Cytoplasm map + SARA*@Early Endosome map
  4. SMAD3@Cytoplasm map + SARA*@Early Endosome map map SARA*:​SMAD3@Early Endosome map
  5. SARA*:​SMAD3@Early Endosome map + ATP@Cytoplasm map map SARA*:​SMAD3|​S423_pho|​S425_pho@Early Endosome map + ADP@Cytoplasm map
  6. SARA*:​SMAD3|​S423_pho|​S425_pho@Early Endosome map map SARA*@Early Endosome map + SMAD3|​S423_pho|​S425_pho@Cytoplasm map
  7. 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

As Catalyser:

  1. SARA*:​SMAD2@Early Endosome map + ATP@Cytoplasm map map SARA*:​SMAD2|​S467_pho|​S465_pho@Early Endosome map + ADP@Cytoplasm map

  2. SARA*:​SMAD3@Early Endosome map + ATP@Cytoplasm map map SARA*:​SMAD3|​S423_pho|​S425_pho@Early Endosome map + ADP@Cytoplasm map

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