TGF-beta receptor signaling
Transforming growth factor beta (TGF-beta) signaling
controls diverse cellular processes, including cell proliferation, differentiation,
adhesion and migration , , .
TGF-beta 1 initiates signaling by binding to and bringing
together type I and type II receptor serine/threonine kinases (TGF-beta
receptor type I and II) on the cell surface.
This allows TGF-beta receptor type II to phosphorylate the
TGF-beta receptor type I kinase domain. TGF-beta receptor
type I then propagates the signal through phosphorylation of the SMAD family member
(SMAD) proteins , . The
recognition of SMADs by TGF-beta receptor type
I may be facilitated by auxiliary protein Zinc finger FYVE domain
containing 9 (SARA) .
SMAD2 and SMAD3 proteins form
hetero-oligomeric complexes with SMAD4. These
translocate to the nucleus and, depending on the cell type and their interactions with
coactivators or corepressors, function as transcriptional modulators , . SMAD3 translocation to the nucleus depends
on binding of Importin (karyopherin)-beta .
Transcription mediated by SMAD2 or
SMAD3 is enhanced by CREB binding protein
(CBP)/E1A binding protein p300
(p300) , .
SMADs can bind DNA directly with low affinity and
specificity and thus rely on interactions with other DNA-binding proteins to target
specific genes for transcriptional regulation, for example Forkhead box H1
(FAST-1/2) . V-ski sarcoma viral oncogene
homolog (Ski) and SKI-like oncogene
(SnoN) modulate the nuclear activity of
SMAD and function as corepressors antagonize
TGF-beta signaling , .
SMAD3-mediated Anaphase-promoting complex with Fizzy/cell
division cycle 20 related 1 (APC/hCDH1 complex) activation
leads to degradation of SnoN . YY1
transcription factor (YY1) as a
SMAD-interacting negatively regulates
TGF-beta signaling . TSC22 domain family
member 1 (TSC-22) as a
SMAD4-interacting positively regulates
TGF-beta-dependent erythroid cell differentiation .
SMAD7 inhibits TGF-beta receptor type
I  via competition with SMAD3
or SMAD2 for binding. SMAD7
interaction leads to the ubiquitination and degradation of the receptors with the help
SMAD specific E3 ubiquitin protein ligase (SMURF).
complex is routed via Caveolin-rich membrane structures and
internalized via Caveolin-positive vesicles toward the
proteasome for degradation. FK506 binding protein 1A 12kDa
(FKBP12) inhibits TGF-beta signaling by binding to the
unphosphorylated GS regions of TGF-beta receptor type I.
This interaction locks the kinase catalytic center of the TGF-beta receptor
type I in an unproductive conformation , .
TGF-beta induces transcription of the human
SMAD7 gene through activation of
SMAD3 , and transcription factor Ets variant
gene 1 (ER81) . Kruppel-like factor 10
(TIEG) represses SMAD7 gene
SMADs functionally cooperate with Sp1 transcription
factor (SP1) to activate the Cyclin-dependent kinase
inhibitor 1A (p21) promoter ,
Cyclin-dependent kinase inhibitor 2B (p15) 
(cell cycle regulation ), Serpin peptidase inhibitor clade E member 1
(PAI1)  (regulation of extracellular matrix
TGF-beta 1 activates p38
MAPK via Mitogen-activated protein kinase kinase kinase 7 interacting
protein 1 (TAB1)  or
SMAD7 / Mitogen-activated protein kinase
kinase kinase 7 (TAK1(MAP3K7))/ Mitogen-activated protein
kinase kinase 3 (MEK3(MAP2K3)). TGF-beta
1 activates, via SMAD3 and
SMAD4, expression of Growth arrest and DNA-damage-inducible
beta (GADD45 beta) that, possibly via Mitogen-activated
protein kinase kinase kinase 4 (MEKK4(MAP3K4)) activates
Mitogen-activated protein kinase kinase 6 (MEK6(MAP2K6)) and
then p38 MAPK .
TGF-beta activates, in p38
MAPK-dependent manner, Antigen identified by monoclonal antibody AJ9
(MSK1) activation , which is known to
phosphorylate TGF-inducible ER81 , . ER81 controls SMAD7
expression and V-erb-b2 erythroblastic leukemia viral oncogene homolog 2
neuro/glioblastoma derived oncogene homolog (ErbB2), which
is also involved in SMAD7 expression regulation .
TGF-beta receptor directly bind SHC transforming protein
1 (Shc) and via possibly V-Ha-ras Harvey rat sarcoma viral
oncogene homolog (H-Ras)/ V-raf-1 murine leukemia viral
oncogene homolog 1 (c-Raf-1)/ mitogen-activated protein
kinase kinase 1 and 2 (MEK1 and
MEK2) activates Mitogen-activated protein kinase 3 and 1
(ERK1/2). This can lead for example to
epithelial-to-mesenchymal transition , , . ERK activates ELK1 member of ETS oncogene family
(Elk-1). Elk-1 transcriptionally activates
p15 expression .
TGF-beta 1 via TAK1(MAP3K7)/ Nuclear factor NFkappaB inhibitor kinases (IKK) inhibition
of Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha
(NFKBIA) activate Nuclear factor kappa B
(NF-kB). As a result of NF-kB
activation, NFKBIA mRNA and protein levels are increased
leading to post-repression of NF-kB and induction of cell
death . TSC-22 stimulates apoptosis too
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