LRIG3 (leucine-rich repeats and Ig-like domains-3) is an ~140-170kD type I transmembrane glycoprotein member of the mammalian LRIG glycoprotein family. This family contains three members who share 45-50% amino acid (aa) identity. All members contain fifteen LRRs, accompanied by two flanking cysteine-rich regions, and three C2-type-Ig-like domains in their extracellular domains (ECD). LRIG3 mRNA is widely expressed, with highest levels in stomach, skin, thyroid and small intestine. Human LRIG3 is synthesized as a 1120 amino acid (aa) precursor. It contains a 24aa signal sequence, a 786aa ECD, a 21aa transmembrane sequence, and a 289aa intracellular region. One splice variant exists that has a 19aa substitution for the first 79aa of the standard (or long) form. This substitution appears to encode an alternate signal sequence, resulting in a mature protein that lacks the first and part of the second LRR. LRIG1, a related family member, is known to bind the EGF family receptors ErbB1-4, via either its LRR or Ig-like domains. It also binds the ubiquitin ligase, c-Cbl, and promotes ubiquitination, internalization and destruction of these receptors. It is not known whether LRIG3 performs similar functions. Within the cell, LRIG3 is expressed in the perinuclear region as well as on the cell surface. Perinuclear location of LRIG3 in grade III and IV astrocytic tumors has been associated with better patient survival. Human LRIG3 ECD shares 91%, 92%, 95% and 98% aa sequence identity with mouse, rat, bovine and canine LRIG3 ECD, respectively.