Bone morphogenetic proteins (BMPs) are the members of the
transforming growth factor-beta superfamily of secreted signaling molecules . BMPs transduce their signals via two signaling pathways: SMAD-dependent
pathway, the so called "canonical" BMP pathway, and SMAD-independent BMP/MAPK cascade
Transduction of BMP signal involves two types of transmembrane
serine/threonine kinase receptors: type I and type II. Bone morphogenetic protein 2, 4, 6
and 7 (BMP2, BMP4,
BMP6 and BMP7) can bind to
three type I receptors: Bone morphogenetic protein receptor, type IA
(BMPR1A), Bone morphogenetic protein
receptor, type IB (BMPR1B) and
Activin A receptor, type I (ALK-2) , , , , , and one type II receptor,
Bone morphogenetic protein receptor type II (BMP receptor 2)
, , .
After ligand binding, BMP receptor 2
recruits and phosphorylates BMPR1A,
BMPR1B and ALK-2, resulting in
the formation of heteromeric ligand/receptor complex. Activated
BMPR1A, BMPR1B and ALK-2
receptors then phosphorylate an appropriate member of Mothers against
decapentaplegic (SMAD) protein family - SMAD family members 1, 5 and 9
(SMAD1, SMAD5 and
SMAD9 (SMAD8)), called receptor-regulated SMADs (R-SMADs),
to elicit cellular responses. Upon phosphorylation, R-SMADs are released from receptors
and interact with SMAD family member 4 (SMAD4).
SMAD4/R-SMAD heteromeric complexes are then translocated
into the nucleus, where SMAD1, SMAD5
and SMAD9 (SMAD8) activate expression of
target genes .
R-SMADs activate transcription of target genes via cooperation
with other transcription factors or via complex formation with general transcriptional
coactivators CREB binding protein (CBP) and E1A binding
protein p300 (p300) , .
BMP-activated SMAD1 interacts with
CBP and p300, and, then,
SMAD1 and p300 /
CBP synergistically activate gene expression . SMAD5 and SMAD9 (SMAD8)
can also form complexes with CBP , . The interaction of R-SMADs with
CBP, activated by cAMP responsive element binding protein 1
(CREB1), results in enhanced transcriptional activity of
Extracellularly, the activity of BMPs can be regulated by
secreted antagonists, such as Chordin,
Noggin, Gremlin 1, cysteine knot superfamily, homolog
(Gremlin), Cerberus 1, cysteine knot superfamily, homolog
(Cerberus), and Follistatin
BMP/ SMAD signaling is also regulated by a variety of
intracellular molecules . The inhibitory SMADs, SMAD family member 6 and
7 (SMAD6 and SMAD7),
can interact with activated type I BMP receptors, and,
thereby, suppress BMP signaling . Thus,
SMAD6 binds to BMPR1B and
inhibits downstream phosphorylation of SMAD1 and
SMAD5 . Moreover,
SMAD6 binds to SMAD1 and prevents the
formation of SMAD4/SMAD1
complex . SMAD7 can bind to
BMPR1A, BMPR1B and ALK-2 and
inhibit downstream phosphorylation of SMAD1 and
SMAD5 , .
SMAD-specific E3 ubiquitin protein ligase 1
(SMURF1) induces ubiquitination and proteasomal degradation
of SMAD1, SMAD5  and BMPR1B . SMAD6
and SMAD7 can form the complex with
SMURF1. This interaction
enhances degradation of SMAD1 and
SMAD5, and as well promotes SMURF1
recruitment to BMPR1B and
subsequent BMPR1B ubiquitination . SMAD-specific E3 ubiquitin protein ligase 2
target SMAD1 for degradation .
V-ski sarcoma viral oncogene homolog
(Ski) interacts with SMAD1,
SMAD5 and SMAD4, thus
repressing BMP signaling , . TOB1 transducer of ERBB2, 1
(Tob1), the member of anti-proliferative protein family, can
directly interact with SMAD1, SMAD5
and SMAD9 (SMAD8), followed by repression of
BMP/SMAD-dependent transcription and, as a consequence, osteogenesis .
Another way for Tob1 inhibitory action is modulating the
function of SMAD6 and SMAD7,
and enhancing the interaction between SMAD6 and
The alternative BMP-induced pathway involves stimulation of
mitogen-activated protein kinases (MAPK). BMPR1A binds to
X-linked inhibitor of apoptosis (XIAP), which, in turn,
recruits TGF-beta activated kinase 1/MAP3K7 binding protein 1
(TAB1). TAB1 activates
Mitogen-activated protein kinase kinase kinase 7 (TAK1)
downstream of BMP2, BMP4 and
BMPR1A , , , . TAK1 then phosphorylates Mitogen-activated
protein kinase kinase 3 and 6 (MEK3 and
MEK6), leading to activation of Mitogen-activated protein
kinase 14 (p38 MAPK) and subsequent stimulation of
Activating transcription factor 2 (ATF-2) , . BMP-induced ATF-2 activation results in
stem cell differentiation , .
SMAD6 binds to TAK1
and inhibits its activity, representing
crosstalk between BMP/SMAD and BMP/MAPK pathways. This interaction leads to blockage of
BMP2-induced p38 MAPK-mediated
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