TGF-beta receptor signaling
Transforming growth factor beta (TGF-beta) signaling
controls diverse cellular processes, including cell proliferation, differentiation,
adhesion and migration [1], [2], [3].
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 [2], [3]. The
recognition of SMADs by TGF-beta receptor type
I may be facilitated by auxiliary protein Zinc finger FYVE domain
containing 9 (SARA) [2].
SMAD2 and SMAD3 proteins form
hetero-oligomeric complexes with SMAD4. These
SMAD2/SMAD4 and
SMAD3/SMAD4 complexes
translocate to the nucleus and, depending on the cell type and their interactions with
coactivators or corepressors, function as transcriptional modulators [3], [4]. SMAD3 translocation to the nucleus depends
on binding of Importin (karyopherin)-beta [5].
Transcription mediated by SMAD2 or
SMAD3 is enhanced by CREB binding protein
(CBP)/E1A binding protein p300
(p300) [6], [7].
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) [8]. 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 [4], [8].
SMAD3-mediated Anaphase-promoting complex with Fizzy/cell
division cycle 20 related 1 (APC/hCDH1 complex) activation
leads to degradation of SnoN [9]. YY1
transcription factor (YY1) as a
SMAD-interacting negatively regulates
TGF-beta signaling [10]. TSC22 domain family
member 1 (TSC-22) as a
SMAD4-interacting positively regulates
TGF-beta-dependent erythroid cell differentiation [11].
SMAD7 inhibits TGF-beta receptor type
I [3] 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).
TGF-beta/SMAD7/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 [2], [4].
TGF-beta induces transcription of the human
SMAD7 gene through activation of
SMAD3 [12], and transcription factor Ets variant
gene 1 (ER81) [13]. Kruppel-like factor 10
(TIEG) represses SMAD7 gene
[14].
SMADs functionally cooperate with Sp1 transcription
factor (SP1) to activate the Cyclin-dependent kinase
inhibitor 1A (p21) promoter [15],
Cyclin-dependent kinase inhibitor 2B (p15) [16]
(cell cycle regulation [17]), Serpin peptidase inhibitor clade E member 1
(PAI1) [18] (regulation of extracellular matrix
[17]).
TGF-beta 1 activates p38
MAPK via Mitogen-activated protein kinase kinase kinase 7 interacting
protein 1 (TAB1) [19] or
SMAD7 [20]/ 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 [21].
TGF-beta activates, in p38
MAPK-dependent manner, Antigen identified by monoclonal antibody AJ9
(MSK1) activation [22], which is known to
phosphorylate TGF-inducible ER81 [13], [23]. 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 [13].
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 [24], [25], [26]. ERK activates ELK1 member of ETS oncogene family
(Elk-1). Elk-1 transcriptionally activates
p15 expression [27].
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 [28]. TSC-22 stimulates apoptosis too
[29], [30].
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