BACKGROUND: The mammalian Vps10p sorting receptor family is a group of 5 type I membrane homologs (Sortilin, SorLA, and SorCS1-3). These receptors bind various cargo proteins via their luminal Vps10p domains and have been shown to mediate a variety of intracellular sorting and trafficking functions. These proteins are highly expressed in the brain. SorLA has been shown to be down regulated in Alzheimer's disease brains, interact with ApoE, and modulate Abeta production. Sortilin has been shown to be part of proNGF mediated death signaling that results from a complex of Sortilin, p75NTR and proNGF. We have investigated and provide evidence for gamma-secretase cleavage of this family of proteins. RESULTS: We provide evidence that these receptors are substrates for presenilin dependent gamma-secretase cleavage. gamma-Secretase cleavage of these sorting receptors is inhibited by gamma-secretase inhibitors and does not occur in PS1/PS2 knockout cells. Like most gamma-secretase substrates, we find that ectodomain shedding precedes gamma-secretase cleavage. The ectodomain cleavage is inhibited by a metalloprotease inhibitor and activated by PMA suggesting that it is mediated by an alpha-secretase like cleavage. CONCLUSION: These data indicate that the alpha- and gamma-secretase cleavages of the mammalian Vps10p sorting receptors occur in a fashion analogous to other known gamma-secretase substrates, and could possibly regulate the biological functions of these proteins.