Molecular cell biology – essay – FOP and
TTC1
Function of the protein encoded by the TTC1 mRNA
The TTC1 or TPR1 gene codes for the tetratricopeptide repeat domain 1 protein
and is expressed in the bone marrow of healthy individuals (Wang et al., 2019).
TTC1 is an adaptor protein and plays a role in protein-protein interactions. It
binds to the Gα of protein-coupled receptors, which leads to a stronger
interaction with the small GTPase Ras and activation of the Ras-signalling
pathway (Liu et al., 2010; Marty et al., 2003). The small GTPase Ras is a central
point in numerous signalling pathways. Ras signals among others to the small
GTPases Rac and Ral, phosphatidylinositol 3 phosphatekinase (P13-K), p38 kinase
(p38K), NF-ϏB pathway and the ERK-activating kinase (MEK)/MAPK axis
(Schindeler & Little, 2006). Those pathways and mediators are involved in the
regulation of many processes, such as: proliferation, cell cycle, oncogenesis,
development and the differentiation in many cell types (Schindeler & Little,
2006).
In the context of Fibrodysplasia ossificans progressive (FOP) or
bone formation in general
The TTC1 plays a role in the activation of the Ras-signalling pathway (Liu et al.,
2010). One of the Ras-signalling pathways is the Ras-MAPK or Ras/Raf-1/MEK/ERK
signalling, which might be essential for the commitment of progenitor cells to
become osteoblasts (Schindeler & Little, 2006). However, it is also possible that
the Ras-MAPK interferes with the activation and nuclear translocation of the
effectors of the Smad-signalling (Schindeler & Little, 2006). However, another
study showed that the Ras-signalling is involved in proliferation of
osteoprogenitor cells and bone formation (Papaioannou, Mirzamohammadi, &
Kobayashi, 2016). We found a downregulation of the TTC1 gene in both controls
and FOP patients after addition of Activin-A, although not significant. The
expression of TTC1 in the condition with addition of Activin-A was significantly
higher in FOP patients compared with controls. According to the above described
pathways (Figure 1) the upregulation of the expression of TTC1 would lead to
more activation of the Ras-MAPK signalling. In addition, the activation of the Ras-
MAPK signalling would lead to activation of Runx2 and transcription of osteogenic
genes. However, the Ras-MAPK signalling could also inhibit the Smad-signalling
leading to less activation of Runx2 and transcription of osteogenic genes (Figure
1). In addition, the BMPs might stimulate the MAPK via an unknown pathway
(Deschaseaux et al., 2009). FOP patients show increased bone formation of soft
tissue. Therefore, we expect that the altered Activin-A receptor type 1 might not
only lead to more bone formation via the Smad 1/5/8 signalling, but also via the
Ras-MAPK signalling. While also the TTC1 expression is upregulated we would
expect the same pathway via the Ras-MAPK and activation of Runx2. This would
lead to even more bone formation.
TTC1
Function of the protein encoded by the TTC1 mRNA
The TTC1 or TPR1 gene codes for the tetratricopeptide repeat domain 1 protein
and is expressed in the bone marrow of healthy individuals (Wang et al., 2019).
TTC1 is an adaptor protein and plays a role in protein-protein interactions. It
binds to the Gα of protein-coupled receptors, which leads to a stronger
interaction with the small GTPase Ras and activation of the Ras-signalling
pathway (Liu et al., 2010; Marty et al., 2003). The small GTPase Ras is a central
point in numerous signalling pathways. Ras signals among others to the small
GTPases Rac and Ral, phosphatidylinositol 3 phosphatekinase (P13-K), p38 kinase
(p38K), NF-ϏB pathway and the ERK-activating kinase (MEK)/MAPK axis
(Schindeler & Little, 2006). Those pathways and mediators are involved in the
regulation of many processes, such as: proliferation, cell cycle, oncogenesis,
development and the differentiation in many cell types (Schindeler & Little,
2006).
In the context of Fibrodysplasia ossificans progressive (FOP) or
bone formation in general
The TTC1 plays a role in the activation of the Ras-signalling pathway (Liu et al.,
2010). One of the Ras-signalling pathways is the Ras-MAPK or Ras/Raf-1/MEK/ERK
signalling, which might be essential for the commitment of progenitor cells to
become osteoblasts (Schindeler & Little, 2006). However, it is also possible that
the Ras-MAPK interferes with the activation and nuclear translocation of the
effectors of the Smad-signalling (Schindeler & Little, 2006). However, another
study showed that the Ras-signalling is involved in proliferation of
osteoprogenitor cells and bone formation (Papaioannou, Mirzamohammadi, &
Kobayashi, 2016). We found a downregulation of the TTC1 gene in both controls
and FOP patients after addition of Activin-A, although not significant. The
expression of TTC1 in the condition with addition of Activin-A was significantly
higher in FOP patients compared with controls. According to the above described
pathways (Figure 1) the upregulation of the expression of TTC1 would lead to
more activation of the Ras-MAPK signalling. In addition, the activation of the Ras-
MAPK signalling would lead to activation of Runx2 and transcription of osteogenic
genes. However, the Ras-MAPK signalling could also inhibit the Smad-signalling
leading to less activation of Runx2 and transcription of osteogenic genes (Figure
1). In addition, the BMPs might stimulate the MAPK via an unknown pathway
(Deschaseaux et al., 2009). FOP patients show increased bone formation of soft
tissue. Therefore, we expect that the altered Activin-A receptor type 1 might not
only lead to more bone formation via the Smad 1/5/8 signalling, but also via the
Ras-MAPK signalling. While also the TTC1 expression is upregulated we would
expect the same pathway via the Ras-MAPK and activation of Runx2. This would
lead to even more bone formation.
