BMPS AND LIVER: MORE QUESTIONS THAN ANSWERS
Blanca Herrera 1*, Aránzazu Sánchez1, Isabel Fabregat2
1. Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense,
Madrid, Spain.
2. Bellvitge Biomedical Research Institute (IDIBELL) and University of Barcelona (UB).
L’Hospitalet, Barcelona, Spain.
* To whom correspondence should be addressed:
Dr. B. Herrera. Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad
Complutense, Plaza Ramón y Cajal S/N, 28040-Madrid, Spain. Phone #: 34-913941854. Fax #: 34
913941779.
Keywords: BMP, liver, signaling, fibrosis, hepatocellular carcinoma, development, iron homeostasis.
Short running title: BMPS in liver
1
,Abstract
Bone morphogenetic proteins (BMPs) belong to the TGF-β superfamily and were first discovered as potent
bone homeostasis regulators for their ability to induce endochondral bone formation, ectopic bone
formation and fracture repair. A preeminent role of BMP signaling in developmental control of cell type
specification, differentiation and organogenesis is also well established.
More recently, a role for BMPs in adult tissue homeostasis have started being revealed. Thus, new studies
show that BMPs regulate many cellular processes such as proliferation, apoptosis, differentiation and
migration in many tissues and organs. As a consequence, dysregulation of BMP activity can have
pathological consequences, and there is mounting evidence for the involvement of BMPs in different
human diseases. In this review, we have focused on summarizing the present knowledge on the relevance
of BMPs in liver physiology and pathophysiology, from the well-recognized role in liver development to
the emerging contribution to the function and dysfunction of the adult liver. While no doubts seem to rise
about the regulatory activities of BMPs on metabolic pathways in the liver, potential pro- and anti-
fibrogenic and tumorigenic actions will likely be a matter of debate during coming years. Collectively, the
work here presented provides the basis to consider BMPs as potential targets of intervention in liver
diseases.
2
,1. Signaling by BMPs
1.1 Ligands secretion and activation
BMPs (Bone morphogenetic proteins) are a large subfamily of the TGF-_ superfamily, comprising more
than 20 members. They are synthesized as large precursor proteins comprised by N-terminal signal peptide,
which directs the protein to the secretory pathway; a prodomain required for proper folding and the C-
terminal mature peptide. The prodomain is usually cleaved by proteases within the Golgi network to
generate the mature active protein. In some cases (i.e., BMP9 and GDF8) the prodomain remains attached
to the mature protein even after secretion, a phenomenon whose consequences are not yet known. Active
BMPs are disulfide-linked homo- or heterodimers. An increased activity of BMP heterodimers both in vitro
and in vivo and/or novel properties have been reported [1-3]. Both the cleavage of the prodomain, which
may interfere with the binding to the receptor, and the formation of homo- or heterodimers constitute two
levels of BMP signaling modulation [4].
1.2 Receptors and co-receptors
BMPs bind to a heterotetrameric complex transmembrane receptor comprised by type I and type II serine
threonine kinase receptors. Both types of receptors contain an N-terminal extracellular ligand binding
domain, a transmembrane region and an intracellular kinase domain. Upon ligand binding, the type II
receptor constitutively active serine-threonine kinase phosphorylates type I receptor within a glycine-serine
rich region (GS box), event that is required for the activation of the type I receptor. Transphosphorylation
of GS box is required for the activation of the type I receptor. Four different type I receptors, also named
activin receptor like kinase (ALK) have been implicated in BMP signaling: ALK1, ALK2, ALK3 (BMPR-
IA) and ALK6 (BMPR-IB). It is also well established that BMPs bind to three distinct type II receptors,
namely BMP type II receptor (BMPRII), activin type II receptor A (ActRIIA) and activin type II receptor B
(ActRIIB) [5, 6]. Despite the fact that different type I and type II receptors present high level of homology,
they are non redundant. Actually, the combinatorial interactions of the different type I and type II receptors
3
, in functional complexes allow for diversity and selectivity in ligand binding as well as intracellular
signaling, which is ultimately responsible for the highly specific functions exerted by the different receptors
[7]. In contrast to TGF−β1 which binds with high affinity to type II receptors, most BMP ligands bind
efficiently to type I receptor. When both type I and type II receptors are present, the binding affinity
increases dramatically. It has been suggested that a small fraction of type II and type I receptors are present
in the cell surface as preformed complexes which may play a role in Smad independent pathways [5, 8, 9].
In addition to type I and type II BMP receptors, co-receptors have been shown to participate in the BMP
response. One of these is Endoglin (Eng), a transmembrane glycoprotein that is expressed mainly in
endothelial cells. Eng is required for TGF-β transduction via type I receptor ALK1, modulating the balance
in ALK1/ALK5 signaling in response to TGF-β in endothelial cells [10-12]. It has been recently shown that
it also participates in BMP9 signaling [13, 14]. Betaglycan is a transmembrane proteoglycan that binds and
presents TGF-β and BMP ligands to the type II and type I receptors, respectively, and modulates BMP
mediated signaling [15-19]. Other co-receptors that enhance BMP signaling are members of the Repulsive
Guidance Molecule family (RGM). RGM molecules modify specific BMP ligands binding affinity for the
BMP type II receptor, thus cells expressing RGM members become more responsive to low concentrations
of specific BMPs [20]. RGM family members and activities are: i) RGMa (or RGM) that enhances BMP2
and BMP4 but not TGF-β or BMP7 signaling, whilst the effect on other BMP ligands have not been
analyzed yet; ii) RGMb (or DRAGON) that enhances BMP signaling, with a greater effect on BMP2 and
BMP4, little effect on BMP5, BMP6 and BMP7 and no effect on BMP9; iii) RGMc (or hemojuvelin) that
has a major role in iron metabolism and is characterized by a strong binding affinity for BMP6. RGMc
presents less affinity for BMP2, BMP4 and BMP5 and little or no effect for BMP7 and BMP9; iv) RGMd,
only expressed in fish [20].
1.4 Extracellular regulators.
Other important modulators of the BMP signaling are the extracellular regulators, soluble secreted proteins
that antagonize or potentiate BMP signaling with a major role in development. The network formed by
Chordin / Tolloid metalloproteinase / Sizzled / Twisted grastrulation / ONT-1/ Crossveinless-2 controls
dorsal-ventral development, creating a dynamic morphogenetic field of BMP activity. Cerberus / Gremlin /
4
Blanca Herrera 1*, Aránzazu Sánchez1, Isabel Fabregat2
1. Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense,
Madrid, Spain.
2. Bellvitge Biomedical Research Institute (IDIBELL) and University of Barcelona (UB).
L’Hospitalet, Barcelona, Spain.
* To whom correspondence should be addressed:
Dr. B. Herrera. Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad
Complutense, Plaza Ramón y Cajal S/N, 28040-Madrid, Spain. Phone #: 34-913941854. Fax #: 34
913941779.
Keywords: BMP, liver, signaling, fibrosis, hepatocellular carcinoma, development, iron homeostasis.
Short running title: BMPS in liver
1
,Abstract
Bone morphogenetic proteins (BMPs) belong to the TGF-β superfamily and were first discovered as potent
bone homeostasis regulators for their ability to induce endochondral bone formation, ectopic bone
formation and fracture repair. A preeminent role of BMP signaling in developmental control of cell type
specification, differentiation and organogenesis is also well established.
More recently, a role for BMPs in adult tissue homeostasis have started being revealed. Thus, new studies
show that BMPs regulate many cellular processes such as proliferation, apoptosis, differentiation and
migration in many tissues and organs. As a consequence, dysregulation of BMP activity can have
pathological consequences, and there is mounting evidence for the involvement of BMPs in different
human diseases. In this review, we have focused on summarizing the present knowledge on the relevance
of BMPs in liver physiology and pathophysiology, from the well-recognized role in liver development to
the emerging contribution to the function and dysfunction of the adult liver. While no doubts seem to rise
about the regulatory activities of BMPs on metabolic pathways in the liver, potential pro- and anti-
fibrogenic and tumorigenic actions will likely be a matter of debate during coming years. Collectively, the
work here presented provides the basis to consider BMPs as potential targets of intervention in liver
diseases.
2
,1. Signaling by BMPs
1.1 Ligands secretion and activation
BMPs (Bone morphogenetic proteins) are a large subfamily of the TGF-_ superfamily, comprising more
than 20 members. They are synthesized as large precursor proteins comprised by N-terminal signal peptide,
which directs the protein to the secretory pathway; a prodomain required for proper folding and the C-
terminal mature peptide. The prodomain is usually cleaved by proteases within the Golgi network to
generate the mature active protein. In some cases (i.e., BMP9 and GDF8) the prodomain remains attached
to the mature protein even after secretion, a phenomenon whose consequences are not yet known. Active
BMPs are disulfide-linked homo- or heterodimers. An increased activity of BMP heterodimers both in vitro
and in vivo and/or novel properties have been reported [1-3]. Both the cleavage of the prodomain, which
may interfere with the binding to the receptor, and the formation of homo- or heterodimers constitute two
levels of BMP signaling modulation [4].
1.2 Receptors and co-receptors
BMPs bind to a heterotetrameric complex transmembrane receptor comprised by type I and type II serine
threonine kinase receptors. Both types of receptors contain an N-terminal extracellular ligand binding
domain, a transmembrane region and an intracellular kinase domain. Upon ligand binding, the type II
receptor constitutively active serine-threonine kinase phosphorylates type I receptor within a glycine-serine
rich region (GS box), event that is required for the activation of the type I receptor. Transphosphorylation
of GS box is required for the activation of the type I receptor. Four different type I receptors, also named
activin receptor like kinase (ALK) have been implicated in BMP signaling: ALK1, ALK2, ALK3 (BMPR-
IA) and ALK6 (BMPR-IB). It is also well established that BMPs bind to three distinct type II receptors,
namely BMP type II receptor (BMPRII), activin type II receptor A (ActRIIA) and activin type II receptor B
(ActRIIB) [5, 6]. Despite the fact that different type I and type II receptors present high level of homology,
they are non redundant. Actually, the combinatorial interactions of the different type I and type II receptors
3
, in functional complexes allow for diversity and selectivity in ligand binding as well as intracellular
signaling, which is ultimately responsible for the highly specific functions exerted by the different receptors
[7]. In contrast to TGF−β1 which binds with high affinity to type II receptors, most BMP ligands bind
efficiently to type I receptor. When both type I and type II receptors are present, the binding affinity
increases dramatically. It has been suggested that a small fraction of type II and type I receptors are present
in the cell surface as preformed complexes which may play a role in Smad independent pathways [5, 8, 9].
In addition to type I and type II BMP receptors, co-receptors have been shown to participate in the BMP
response. One of these is Endoglin (Eng), a transmembrane glycoprotein that is expressed mainly in
endothelial cells. Eng is required for TGF-β transduction via type I receptor ALK1, modulating the balance
in ALK1/ALK5 signaling in response to TGF-β in endothelial cells [10-12]. It has been recently shown that
it also participates in BMP9 signaling [13, 14]. Betaglycan is a transmembrane proteoglycan that binds and
presents TGF-β and BMP ligands to the type II and type I receptors, respectively, and modulates BMP
mediated signaling [15-19]. Other co-receptors that enhance BMP signaling are members of the Repulsive
Guidance Molecule family (RGM). RGM molecules modify specific BMP ligands binding affinity for the
BMP type II receptor, thus cells expressing RGM members become more responsive to low concentrations
of specific BMPs [20]. RGM family members and activities are: i) RGMa (or RGM) that enhances BMP2
and BMP4 but not TGF-β or BMP7 signaling, whilst the effect on other BMP ligands have not been
analyzed yet; ii) RGMb (or DRAGON) that enhances BMP signaling, with a greater effect on BMP2 and
BMP4, little effect on BMP5, BMP6 and BMP7 and no effect on BMP9; iii) RGMc (or hemojuvelin) that
has a major role in iron metabolism and is characterized by a strong binding affinity for BMP6. RGMc
presents less affinity for BMP2, BMP4 and BMP5 and little or no effect for BMP7 and BMP9; iv) RGMd,
only expressed in fish [20].
1.4 Extracellular regulators.
Other important modulators of the BMP signaling are the extracellular regulators, soluble secreted proteins
that antagonize or potentiate BMP signaling with a major role in development. The network formed by
Chordin / Tolloid metalloproteinase / Sizzled / Twisted grastrulation / ONT-1/ Crossveinless-2 controls
dorsal-ventral development, creating a dynamic morphogenetic field of BMP activity. Cerberus / Gremlin /
4
