Leucine-rich repeat-containing protein 4 (LRRC4)

Leucine-rich repeat-containing protein 4 (LRRC4, also known as NGL-2 or netrin-G ligand-2) is a neuronally enriched, type I transmembrane cell adhesion molecule belonging to the leucine-rich repeat (LRR) superfamily. Highly expressed in the brain, it is essential for excitatory synapse formation, axonal polarization, and synaptic plasticity, impacting memory formation and storage. LRRC4 mediates cross-synaptic interactions with netrin-G2 and postsynaptic scaffolding proteins like PSD95, modulating recruitment of key ionotropic glutamate receptors. Functionally, LRRC4 also acts as a tumor suppressor: its expression is lost or reduced in several cancers (notably glioma/glioblastoma, nasopharyngeal carcinoma, ovarian cancer, and hepatocellular carcinoma), where it inhibits cell proliferation, migration, invasion, and autophagy by antagonizing multiple signaling pathways (including ERK, PI3K/Akt, NF-κB, STAT3, and JNK). Aberrant LRRC4 regulation is implicated in central nervous system pathologies such as autism spectrum disorder and spinal cord injury, where it is neuroprotective and modulates immune cell infiltration. Restoration of LRRC4 can enhance glioma sensitivity to chemotherapeutics (temozolomide) and may serve as both a diagnostic/prognostic cancer biomarker and a potential therapeutic target in oncology and neurological diseases[1][2].

Other names

NGL-2Netrin-G ligand-2NAG14Brain tumor-associated protein BAGNasopharyngeal carcinoma-associated gene 14 proteinUNQ554/PRO1111netrin-G2 ligandLRRC4B (note: sometimes confused, but LRRC4B is NGL-3)Leucine-rich repeat containing 4

Tumor suppression via inhibition of ERK/Akt/NF-κB/STAT3 pathways, Inhibition of autophagy, Enhancement of chemosensitivity (temozolomide), Regulation of synapse formation and plasticity, Inhibition of malignant cell proliferation and invasion