Abstract
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic ossification in muscle tissues. Constitutively activated mutants of a bone morphogenetic protein (BMP) receptor, ALK2, have been identified in patients with FOP. Recently, a novel ALK2 mutation, L196P, was found in the most benign case of FOP reported thus far. In the present study, we examined the biological activities of ALK2(L196P) in vitro. Over-expression of ALK2(L196P) induced BMP-specific activities, including the suppression of myogenesis, the induction of alkaline phosphatase activity, increased BMP-specific luciferase reporter activity, and increased phosphorylation of Smad1/5 but not Erk1/2 or p38. The activities of ALK2(L196P) were higher than those of ALK2(G356D), another mutant ALK2 allele found in patients with FOP and were equivalent to those of ALK2(R206H), a typical mutation found in patients with FOP. ALK2(L196P) was equally or more resistant to inhibitors in comparison to ALK2(R206H). These findings suggest that ALK2(L196P) is an activated BMP receptor equivalent to ALK2(R206H) and that ALK2(L196P) activity may be suppressed in vivo by a novel molecular mechanism in patients with this mutation.
| Original language | English |
|---|---|
| Pages (from-to) | 213-218 |
| Number of pages | 6 |
| Journal | Biochemical and Biophysical Research Communications |
| Volume | 407 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Apr 1 2011 |
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All Science Journal Classification (ASJC) codes
- Biophysics
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
A novel mutation of ALK2, L196P, found in the most benign case of fibrodysplasia ossificans progressiva activates BMP-specific intracellular signaling equivalent to a typical mutation, R206H. / Ohte, Satoshi; Shin, Masashi; Sasanuma, Hiroki; Yoneyama, Katsumi; Akita, Masumi; Ikebuchi, Kenji; Jimi, Eijiro; Maruki, Yuichi; Matsuoka, Masaru; Namba, Akira; Tomoda, Hiroshi; Okazaki, Yasushi; Ohtake, Akira; Oda, Hiromi; Owan, Ichiro; Yoda, Tetsuya; Furuya, Hirokazu; Kamizono, Jyunji; Kitoh, Hiroshi; Nakashima, Yasuharu; Susami, Takafumi; Haga, Nobuhiko; Komori, Tetsuo; Katagiri, Takenobu.
In: Biochemical and Biophysical Research Communications, Vol. 407, No. 1, 01.04.2011, p. 213-218.Research output: Contribution to journal › Article
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TY - JOUR
T1 - A novel mutation of ALK2, L196P, found in the most benign case of fibrodysplasia ossificans progressiva activates BMP-specific intracellular signaling equivalent to a typical mutation, R206H
AU - Ohte, Satoshi
AU - Shin, Masashi
AU - Sasanuma, Hiroki
AU - Yoneyama, Katsumi
AU - Akita, Masumi
AU - Ikebuchi, Kenji
AU - Jimi, Eijiro
AU - Maruki, Yuichi
AU - Matsuoka, Masaru
AU - Namba, Akira
AU - Tomoda, Hiroshi
AU - Okazaki, Yasushi
AU - Ohtake, Akira
AU - Oda, Hiromi
AU - Owan, Ichiro
AU - Yoda, Tetsuya
AU - Furuya, Hirokazu
AU - Kamizono, Jyunji
AU - Kitoh, Hiroshi
AU - Nakashima, Yasuharu
AU - Susami, Takafumi
AU - Haga, Nobuhiko
AU - Komori, Tetsuo
AU - Katagiri, Takenobu
PY - 2011/4/1
Y1 - 2011/4/1
N2 - Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic ossification in muscle tissues. Constitutively activated mutants of a bone morphogenetic protein (BMP) receptor, ALK2, have been identified in patients with FOP. Recently, a novel ALK2 mutation, L196P, was found in the most benign case of FOP reported thus far. In the present study, we examined the biological activities of ALK2(L196P) in vitro. Over-expression of ALK2(L196P) induced BMP-specific activities, including the suppression of myogenesis, the induction of alkaline phosphatase activity, increased BMP-specific luciferase reporter activity, and increased phosphorylation of Smad1/5 but not Erk1/2 or p38. The activities of ALK2(L196P) were higher than those of ALK2(G356D), another mutant ALK2 allele found in patients with FOP and were equivalent to those of ALK2(R206H), a typical mutation found in patients with FOP. ALK2(L196P) was equally or more resistant to inhibitors in comparison to ALK2(R206H). These findings suggest that ALK2(L196P) is an activated BMP receptor equivalent to ALK2(R206H) and that ALK2(L196P) activity may be suppressed in vivo by a novel molecular mechanism in patients with this mutation.
AB - Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic ossification in muscle tissues. Constitutively activated mutants of a bone morphogenetic protein (BMP) receptor, ALK2, have been identified in patients with FOP. Recently, a novel ALK2 mutation, L196P, was found in the most benign case of FOP reported thus far. In the present study, we examined the biological activities of ALK2(L196P) in vitro. Over-expression of ALK2(L196P) induced BMP-specific activities, including the suppression of myogenesis, the induction of alkaline phosphatase activity, increased BMP-specific luciferase reporter activity, and increased phosphorylation of Smad1/5 but not Erk1/2 or p38. The activities of ALK2(L196P) were higher than those of ALK2(G356D), another mutant ALK2 allele found in patients with FOP and were equivalent to those of ALK2(R206H), a typical mutation found in patients with FOP. ALK2(L196P) was equally or more resistant to inhibitors in comparison to ALK2(R206H). These findings suggest that ALK2(L196P) is an activated BMP receptor equivalent to ALK2(R206H) and that ALK2(L196P) activity may be suppressed in vivo by a novel molecular mechanism in patients with this mutation.
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UR - http://www.scopus.com/inward/citedby.url?scp=79953163208&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2011.03.001
DO - 10.1016/j.bbrc.2011.03.001
M3 - Article
VL - 407
SP - 213
EP - 218
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 1
ER -