ALK5

ALK5, short for Activin receptor-like kinase 5, is also known as TGF-β type I receptor (TGFBR1). It is a type I serine/threonine kinase receptor in the transforming growth factor beta (TGF-β) signaling pathway and is widely expressed in human tissues. ALK5 forms a receptor complex with type II TGF-β receptors; upon ligand binding, the type II receptor phosphorylates ALK5, activating its kinase domain.

In the canonical signaling pathway, activated ALK5 phosphorylates SMAD2 and SMAD3, which then partner with SMAD4 and translocate to the nucleus to regulate gene transcription. Non-SMAD pathways, including MAPK, PI3K/Akt, and Rho-like GTPase signaling, can also be engaged downstream of ALK5. TGF-β ligands such as TGF-β1, TGF-β2, and TGF-β3 primarily signal through this receptor complex.

ALK5 plays a central role in development, tissue homeostasis, and wound healing. Dysregulation of ALK5 signaling is implicated in fibrosis (lung, liver, kidney), vascular and immune disorders, and cancer, where TGF-β signaling can promote epithelial-mesenchymal transition and metastasis in certain contexts. Because of its involvement in fibrotic and oncogenic processes, ALK5 is a target of therapeutic interest.

Inhibitors targeting ALK5 include small molecules such as galunisertib (LY2157299), vactosertib (TEW-7197), and research tools like SB-431542. These agents are used to study TGF-β–driven pathology and explored in clinical trials for fibrotic diseases and cancer. The TGFBR1 gene encodes the ALK5 protein, which features an extracellular ligand-binding domain, a transmembrane segment, and an intracellular kinase domain.