LRRC4, a novel member of LRR (leucine-rich repeat) superfamily, is cloned by expressed sequence tag (EST)-mediated positional cloning strategy combined with 5′-RACE technology. Normal expression of LRRC4 is highly specific for brain, whereas absent or significantly down-regulated in primary tumors including glioma, meningioma and pituitary adenoma. LRRC4 is a functional gene in neural development and axon growth, and associated with glioma grade progression. LRRC4 expression is gradually reduced, even absent accompany with glioma grade increase. Absent expression of LRRC4 is involved in the late event of malignant glioma progression.The reexpression of LRRC4 can decrease a series of growth factors/neurotrophic factors (IGF, EGF, PDGF, CNTF, bFGF,GDNF and BDNF) or receptors gene expression to regulate RTK-mediated many signaling transduction pathway, such as K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF-κB, p70S6/PKC, STAT3 and JNK2/c-Jun/mp53, which block U251 cells in late phase of G1 to inhibit glioma cells proliferation and invasion. This inhibitory effect of LRRC4 is dependent on its LRR domain. LRRC4 induces glioma cells to differentiate into astrocyte-like cells more than apoptosis.