Follistatin

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Cat Number

92530ES

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Product Detail Description Scientific Support Advanced Innovations Customer Q&A

Synonyms

FS; FSActivin-binding protein; FST

Molecular Weight

Approximately 31.5 kDa.

Appearance

Sterile filtered white lyophilized (freeze-dried) powder.

General Description

Mature follistatin is composed of an N-terminal distinct domain (Fs0), and three follistatin domains (Fs1, 2, 3). There are three main isoforms of follistatin that have different C-terminal tails. These isoforms are produced through various combinations of alternative splicing and proteolytic processing. The main functional difference between isoforms is in their binding affinity towards heparan sulphates (HS). The shortest isoform (Fs288) has the highest affinity for HS, while the longest isoform (Fs315) with its acidic tail has no ability to bind HS.

Mechanism of Action

Follistatin modulates TGFβ signaling by binding several ligands of TGFβ including myostatin, activin A, BMPs and GDFs. It complexes with the ligands in a nearly irreversible interaction, whereby follistatin traps the ligand within its structure. By trapping the ligand, follistatin prevents them from binding to type I/type II receptors and inhibits signaling. Because of this, follistatin can neutralize FSH. The heparin-binding site allows follistatin to bind to proteoglycans, increasing its interactions with the extracellular matrix.

Application

Because follistatin inhibits myostatin, follistatin therapies are potential treatments for muscle-wasting diseases such as muscular dystrophy and sarcopenia. Neutralization of activin and BMPs also may have therapeutic potential in diseases of reproduction, osteoporosis, and metabolic syndromes.

Follistatin expression is also controlled by additional layer(s) of regulatory control outside of the basal TGF-β-Smad autoregulatory feedback circuit often disrupted in cancer. Follistatin upregulation in head and neck squamous cell carcinoma (HNSCC) arises through MAPK signaling mediated by EGFR and TP63 amplification, likely at super-enhancers reprogramming the epigenetic landscape. Inactivating mutations of FAT1 also impair Hippo pathway signaling allowing YAP1 translocation to the nucleus where it forms a complex with TEAD and BRD4 that binds to the follistatin promoter to drive tumorigenesis and immune evasion. Pharmacologic inhibition of BRD4 (i.e. BET inhibitors like JQ1) blocks YAP-mediated follistatin upregulation. Follistatin also functions as a transcriptional coregulator of TEAD/p63-mediated immune evasion programs contributing to an immunosuppressive TME. Taken together, oncogenic dependency on follistatin links epithelial-stromal communication with immune-cold, therapeutic drug-resistant tumor microenvironments in squamous cancers.

Fig. 1 Signaling pathways driving follistatin in cancer. (Sosa J, et al. 2024)

References

Sosa J, et al. The reign of follistatin in tumors and their microenvironment: implications for drug resistance. Biology. 2024, 13(2): 130.

A therapy to silence activin A (ActA) due to its overexpression was created by loading LNPs with follistatin (FST) mRNA. In vivo studies of the murine model of head and neck squamous cell carcinoma (HNSCC) showed LNPs delivering FST mRNA resulted in local and systemic downregulation of ActA expression which decreased tumor burden and metastasis to the lungs, as well as inhibited cachexia-related loss of muscle and adipose tissue mass. mRNA LNPs encoding FST were based on ALC-0315 and utilized mRNA modified with pseudouridine to ensure a safety profile conducive to effective FST expression. ActA overexpression is implicated in the formation of metastasis as well as cachexia in multiple cancers, so both routes of administration were effective including IP delivery and localized transfection of tumors when administered SC.

Fig. 2 Inhibition of head and neck squamous cell carcinoma metastasis using follistatin mRNA lipid nanoparticles. (Grigoriev V, et al. 2024)

References

Grigoriev V, et al. Targeting metastasis in head and neck squamous cell carcinoma using follistatin mRNA lipid nanoparticles. ACS nano. 2024, 18(49): 33330-33347.

Can I freeze-thaw the reconstituted Follistatin solution multiple times?

No, please aliquot the Follistatin solution into single-use vials to avoid repeated freeze-thaw cycles.

What information is needed to place a Follistatin purchase order?

Please provide the catalog number, quantity, shipping address, and billing details for your Follistatin order.

Can I modify my Follistatin order after it has been placed?

Modifications are possible if the Follistatin has not yet entered the shipping or production phase.

How will I receive the tracking number for my Follistatin shipment?

We will email the tracking link as soon as your Follistatin package is picked up by the courier.