Related Experiment Video

Updated: Jun 3, 2026

Visualization and Quantification of TGFβ/BMP/SMAD Signaling under Different Fluid Shear Stress Conditions using Proximity-Ligation-Assay
11:38

Visualization and Quantification of TGFβ/BMP/SMAD Signaling under Different Fluid Shear Stress Conditions using Proximity-Ligation-Assay

Published on: September 14, 2021

Activation of the activin A-ALK-Smad pathway in systemic sclerosis

Kae Takagi1, Yasushi Kawaguchi, Manabu Kawamoto

  • 1Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan.

Journal of Autoimmunity
|March 8, 2011
PubMed

Insights

Systemic sclerosis (SSc) involves fibrosis, with activin A and its receptor ACVRIB/ALK4 playing a key role. Inhibiting this pathway may offer a novel therapeutic strategy for SSc patients.

Area of Science:

  • Fibrosis research
  • Connective tissue disorders
  • Molecular mechanisms of disease

Background:

  • Systemic sclerosis (SSc) is a chronic, fibrotic disease of unknown cause.
  • Transforming Growth Factor-beta (TGF-β) is implicated in fibrosis, but mechanisms remain unclear.
  • Activin, a TGF-β superfamily member, is investigated for its role in SSc pathogenesis.

Purpose of the Study:

  • To investigate the role of activin A and its signaling pathway (ACVRIB/ALK4) in systemic sclerosis (SSc).
  • To explore the potential of targeting the activin A-ACVRIB/ALK4-Smad pathway as a therapeutic strategy for SSc.

Main Methods:

  • Serum activin A levels measured by ELISA in SSc patients and controls.
  • Expression of activin receptor type IB (ACVRIB/ALK4) analyzed via Western blotting.
  • Activin A stimulation and ALK4/5 inhibitor (SB431542) used to assess pathway activity in SSc fibroblasts.

Main Results:

  • SSc patients exhibited significantly higher serum activin A levels.
  • Elevated activin A and ACVRIB/ALK4 expression found in SSc fibroblasts.
  • Activin A stimulation increased Smad2/3 phosphorylation, CTGF expression, and collagen production in SSc fibroblasts.
  • Inhibition of ALK4/5 blocked Smad2/3 phosphorylation and CTGF expression.

Conclusions:

  • The activin A-ACVRIB/ALK4-Smad pathway is upregulated and contributes to collagen production in SSc.
  • This pathway is a potential therapeutic target for treating systemic sclerosis.
  • Inhibiting the activin A-ACVRIB/ALK4-Smad pathway presents a novel treatment approach for SSc.

Related Concept Videos

TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
Intracellular Signaling Affects Focal Adhesions01:17

Intracellular Signaling Affects Focal Adhesions

Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...
Activation of Integrins01:15

Activation of Integrins

Integrins bind ligands and transmit information from outside the cell to inside or vice-versa through an "outside-in signaling" or "inside-out signaling."
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding events provide an effective stimulus.
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Non-Canonical Wnt Signaling Pathways01:41

Non-Canonical Wnt Signaling Pathways

Wnt is a zygotic effect gene that is expressed during very early embryonic development. It regulates various processes in animals starting from early development through the adult stage, such as organogenesis in the embryo and maintenance of neuronal and blood stem cells. Wnt proteins can induce a wide variety of intracellular pathways depending upon the specific abilities of different Wnt ligands to form a complex with shared and cognate receptors in the presence of different co-receptors. The...