Development - BMP signaling

BMP signaling

Bone morphogenetic proteins (BMPs) are the members of the transforming growth factor-beta superfamily of secreted signaling molecules [1]. BMPs transduce their signals via two signaling pathways: SMAD-dependent pathway, the so called "canonical" BMP pathway, and SMAD-independent BMP/MAPK cascade [2].

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) [1], [3], [4], [5], [6], and one type II receptor, Bone morphogenetic protein receptor type II (BMP receptor 2) [6], [7], [8].

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 [2].

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) [9], [10]. BMP-activated SMAD1 interacts with CBP and p300, and, then, SMAD1 and p300 / CBP synergistically activate gene expression [11]. SMAD5 and SMAD9 (SMAD8) can also form complexes with CBP [12], [13]. The interaction of R-SMADs with CBP, activated by cAMP responsive element binding protein 1 (CREB1), results in enhanced transcriptional activity of R-SMADs [13].

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 [14].

BMP/ SMAD signaling is also regulated by a variety of intracellular molecules [2]. 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 [2]. Thus, SMAD6 binds to BMPR1B and inhibits downstream phosphorylation of SMAD1 and SMAD5 [15]. Moreover, SMAD6 binds to SMAD1 and prevents the formation of SMAD4/SMAD1 complex [16]. SMAD7 can bind to BMPR1A, BMPR1B and ALK-2 and inhibit downstream phosphorylation of SMAD1 and SMAD5 [17], [18].

SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) induces ubiquitination and proteasomal degradation of SMAD1, SMAD5 [19] and BMPR1B [20]. 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 [20]. SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2) can target SMAD1 for degradation [21].

V-ski sarcoma viral oncogene homolog (Ski) interacts with SMAD1, SMAD5 and SMAD4, thus repressing BMP signaling [22], [23]. 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 [24]. Another way for Tob1 inhibitory action is modulating the function of SMAD6 and SMAD7, and enhancing the interaction between SMAD6 and BMPR1B [25].

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 [26], [27], [28], [29]. 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) [30], [31]. BMP-induced ATF-2 activation results in stem cell differentiation [32], [33].

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 apoptosis [34].

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