Mesencephalic astrocyte-derived neurotrophic factor (MANF), also known as arginine-rich, mutated in early stage tumors (ARMET) and arginine-rich protein (ARP), is a 20 kDa member of the ARMET family of proteins. The name ARMET comes from the fact that the protein was initially thought to be 50 aa longer at the N-terminus and to contain an arginine-rich region. The presence of a specific mutation changing the previously numbered codon 50 from ATG to AGG, or deletion of that codon, has been reported in a variety of solid tumors. Human MANF is synthesized as a 179 amino acid (aa) precursor that contains a 21 aa signal sequence and a
158 aa mature chain. Mature human MANF is 99%, 98% and 96% aa identical to mature rat, mouse and bovine MANF, respectively. MANF is localized to the endoplasmic reticulum (ER) and Golgi apparatus, and is also secreted. In the CNS, MANF selectively protects nigral dopaminergic neurons, versus GABAergic or serotonergic neurons, which suggests that MANF may be indicated for the treatment of Parkinson’s disease. MANF is also one of the 12 commonly unfolded protein response (UPR)-up-regulated genes. One study showed that MANF plays an important role in protecting cells against tunicamycin and thapsigargin-induced cell death. Loss of MANF renders cells more susceptible to those drugs, but also increases cell proliferation and decreases cell size. Another study showed that MANF is an endoplasmic reticulum stress response (ERSR) gene in the heart that can be induced and secreted in response to ER stresses, including ischemia, and that extracellular MANF may protect cardiac myocytes in an autocrine and paracrine manner.
