E3 ubiquitin-protein ligase Arkadia

Gene
Rnf111
Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score:-Experimental evidence at protein level i

Function i

E3 ubiquitin-protein ligase required for mesoderm patterning during embryonic development

(PubMed:11298452). Acts as an enhancer of the transcriptional responses of the
SMAD2/SMAD3 effectors, which are activated downstream of BMP (PubMed:14657019).
Acts by mediating ubiquitination and degradation of SMAD inhibitors such as SMAD7,
inducing their proteasomal degradation and thereby enhancing the transcriptional activity of
TGF-beta and BMP (PubMed:14657019). In addition to enhance transcription of
SMAD2/SMAD3 effectors, also regulates their turnover by mediating their ubiquitination and
subsequent degradation, coupling their activation with degradation, thereby ensuring that
only effectors 'in use' are degraded (By similarity). Activates SMAD3/SMAD4-dependent
transcription by triggering signal-induced degradation of SNON isoform of SKIL (By
similarity). Associates with UBE2D2 as an E2 enzyme (By similarity). Specifically binds
polysumoylated chains via SUMO interaction motifs (SIMs) and mediates ubiquitination of
sumoylated substrates (PubMed:23530056). Catalyzes 'Lys-63'-linked ubiquitination of
sumoylated XPC in response to UV irradiation, promoting nucleotide excision repair (By
similarity). Mediates ubiquitination and degradation of sumoylated PML
(PubMed:23530056). The regulation of the BMP-SMAD signaling is however independent of
sumoylation and is not dependent of SUMO interaction motifs (SIMs)
(PubMed:23530056).By similarity4 Publications
Catalytic activityi

 S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-

lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor
protein]-L-lysine.1 Publication EC:2.3.2.27
Activity regulationi
Binds free ubiquitin non-covalently via its RING-type zinc finger. Ubiquitin-binding leads to
enhance the E3 ubiquitin-protein ligase activity by stabilizing the ubiquitin-conjugating
enzyme E2 (donor ubiquitin) in the 'closed' conformation and activating ubiquitin transfer. By
similarity
Pathwayi: protein ubiquitination
This protein is involved in the pathway protein ubiquitination, which is part of Protein
modification.
View all proteins of this organism that are known to be involved in the pathway protein
ubiquitination and in Protein modification.
Arkadia amplifies TGF-beta superfamily signaling
through degradation of Smad7.
Koinuma D., Shinozaki M., Komuro A., Goto K., Saitoh M., Hanyu A., Ebina M., Nukiwa
T., Miyazawa K., Imamura T., Miyazono K.

Arkadia was originally identified as a protein that enhances signalling activity of Nodal and
induces mammalian nodes during early embryogenesis; however, the mechanisms by
which Arkadia affects transforming growth factor-beta (TGF-beta) superfamily
signalling have not been determined. Here we show that Arkadia is widely expressed in
mammalian tissues, and that it enhances both TGF-beta and bone morphogenetic protein
(BMP) signalling. Arkadia physically interacts with inhibitory Smad, Smad7, and induces its
poly-ubiquitination and degradation. In contrast to Smurf1, which interacts with TGF-beta
receptor complexes through Smad7 and degrades them, Arkadia fails to associate with
TGF-beta receptors. In contrast to Smad7, expression of Arkadia is down-regulated by
TGF-beta. Silencing of the Arkadia gene resulted in repression of transcriptional activities
induced by TGF-beta and BMP, and accumulation of the Smad7 protein. Arkadia may thus
play an important role as an amplifier of TGF-beta superfamily signalling under both
physiological and pathological conditions.

Rnf111
Name: ring finger protein 111
Description: Exhibits SMAD binding activity. Predicted to be involved in several processes, including cellular
protein metabolic process; positive regulation of nitrogen compound metabolic process; and
positive regulation of transforming growth factor beta receptor signaling pathway. Predicted to
localize to the cytosol; nucleus; and protein-containing complex. Orthologous to human RNF111
(ring finger protein 111); PARTICIPATES IN transforming growth factor-beta Smad dependent
signaling pathway; INTERACTS WITH (S)-10-[(DIMETHYLAMINO)METHYL]-4-ETHYL-4,9-
DIHYDROXY-1H-PYRANO[3',4':6,7]INOLIZINO[1,2-B]-QUINOLINE-3,14(4H,12H)-DIONE; 2,4-
dinitrotoluene; bisphenol A.
Type: protein-coding
RefSeq Status: PROVISIONAL
Also known as: E3 ubiquitin-protein ligase Arkadia; LOC300813; ring finger 111
Transforming growth factor beta-1

proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth

factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of
TGF-beta-1, respectively.1 Publication1 Publication
Latency-associated peptide: Required to maintain the Transforming growth factor beta-1
(TGF-beta-1) chain in a latent state during storage in extracellular matrix
(PubMed:28117447). Associates non-covalently with TGF-beta-1 and regulates its activation
via interaction with 'milieu molecules', such as LTBP1, LRRC32/GARP and LRRC33/NRROS,
that control activation of TGF-beta-1 (PubMed:2022183, PubMed:8617200,
PubMed:8939931, PubMed:19750484, PubMed:22278742, PubMed:19651619). Interaction
with LRRC33/NRROS regulates activation of TGF-beta-1 in macrophages and microglia
(Probable). Interaction with LRRC32/GARP controls activation of TGF-beta-1 on the surface
of activated regulatory T-cells (Tregs) (PubMed:19750484, PubMed:22278742,
PubMed:19651619). Interaction with integrins (ITGAV:ITGB6 or ITGAV:ITGB8) results in
distortion of the Latency-associated peptide chain and subsequent release of the active TGF-
beta-1 (PubMed:22278742, PubMed:28117447).1 Publication7 Publications

Transforming growth factor beta-1: Multifunctional protein that regulates the growth
and differentiation of various cell types and is involved in various processes, such
as normal development, immune function, microglia function and responses to
neurodegeneration (By similarity). Activation into mature form follows different steps:
following cleavage of the proprotein in the Golgi apparatus, Latency-associated peptide
(LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains remain non-covalently
linked rendering TGF-beta-1 inactive during storage in extracellular matrix
(PubMed:29109152). At the same time, LAP chain interacts with 'milieu molecules', such as
LTBP1, LRRC32/GARP and LRRC33/NRROS that control activation of TGF-beta-1 and
maintain it in a latent state during storage in extracellular milieus (PubMed:2022183,
PubMed:8617200, PubMed:8939931, PubMed:19750484, PubMed:22278742,
PubMed:19651619). TGF-beta-1 is released from LAP by integrins (ITGAV:ITGB6 or
ITGAV:ITGB8): integrin-binding to LAP stabilizes an alternative conformation of the LAP
bowtie tail and results in distortion of the LAP chain and subsequent release of the active
TGF-beta-1 (PubMed:22278742, PubMed:28117447). Once activated following release of
LAP, TGF-beta-1 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which
transduce signal (PubMed:20207738). While expressed by many cells types, TGF-beta-1
only has a very localized range of action within cell environment thanks to fine regulation of
its activation by Latency-associated peptide chain (LAP) and 'milieu molecules' (By
similarity). Plays an important role in bone remodeling: acts as a potent stimulator of
osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in
committed osteoblasts (By similarity). Can promote either T-helper 17 cells (Th17) or
regulatory T-cells (Treg) lineage differentiation in a concentration-dependent manner (By
similarity). At high concentrations, leads to FOXP3-mediated suppression of RORC and
down-regulation of IL-17 expression, favoring Treg cell development (By similarity). At low
concentrations in concert with IL-6 and IL-21, leads to expression of the IL-17 and IL-23
receptors, favoring differentiation to Th17 cells (By similarity). Stimulates sustained
production of collagen through the activation of CREB3L1 by regulated intramembrane
proteolysis (RIP) (PubMed:25310401). Mediates SMAD2/3 activation by inducing its
phosphorylation and subsequent translocation to the nucleus (PubMed:25893292,
PubMed:29483653). Can induce epithelial-to-mesenchymal transition (EMT) and cell
migration in various cell types (PubMed:25893292).