FHL3 Gene - Four and a Half LIM Domains 3 | Function, Mutations & Disease

FHL3 (Four and a Half LIM Domains 3) encodes a member of the four-and-a-half-LIM-only protein family. The protein contains four and a half LIM domains, which are zinc-binding motifs involved in protein-protein interactions. FHL3 is predominantly expressed in skeletal and cardiac muscle and functions as a transcriptional co-regulator, modulating myogenic differentiation and cytoskeletal organization. It interacts with transcription factors such as MyoD and MEF2, and with structural proteins like integrins and actin, influencing cell adhesion, migration, and muscle fiber integrity.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Integrin signaling pathway (Reactome: R-HSA-354192)

• Myogenesis (Reactome: R-HSA-525793)

• MEF2D-mediated transcription (Reactome: R-HSA-9617629)

• p130Cas linkage to MAPK signaling for integrins (Reactome: R-HSA-372708)

FHL3 is a 279-amino-acid protein (UniProt Q13643) containing four complete LIM domains and one N-terminal half LIM domain. Each LIM domain coordinates two zinc ions, forming a double zinc-finger structure that mediates specific protein interactions. FHL3 shuttles between the cytoplasm and nucleus, acting as an adaptor that links structural proteins (e.g., integrins, actin) to transcriptional regulators (e.g., MyoD, MEF2). In muscle, it promotes myoblast differentiation and sarcomere assembly. In cancer, FHL3 can either suppress or promote tumor progression depending on context: loss contributes to metastasis in colorectal cancer, while overexpression enhances invasion in rhabdomyosarcoma.