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BMPS AND LIVER: MORE QUESTIONS THAN ANSWERS

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bmps and liver more questions than answers
blanca herrera 1 aránzazu sánchez1 isabel fabre
12 receptors and co receptors

Institution BMPS AND LIVER
Course BMPS AND LIVER

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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 /

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