Phosphatidylinositol 3-kinase and Akt protein kinase mediate IGF-I- and prosaptide-induced survival in Schwann cells

Withdrawal of trophic factors necessary for Schwann cell survival regulates Schwann cell number during development and after nerve injury. In the pres ent study, we identified signaling pathways involved in Schwann cell surviv al by prosaposin, prosaptides (peptides incorporating the neurotrophic sequ ence of prosaposin), and insulinlike growth factor-I (IGF-I), When postnata l Schwann cells were placed in low serum medium, cells underwent abrupt shr inkage, condensation of nuclei occurred, and smooth rounded apoptotic bodie s appeared. Dose-response studies of cell death, measured by lactate dehydr ogenase (LDH) release, demonstrated that both prosaptide TX14(A) and IGP-I dose dependently reduced cell death in primary Schwann cells. Histone-assoc iated DNA fragmentation enzyme-linked immunosorbent assay, showed a 10- and 14-fold increase in apoptosis after 4 and 24 hr in low serum medium, respe ctively, that was reduced by prosaposin, TX14(A), or IGF-I, Phosphatidylino sitol 3-kinase (PI3K) inhibitors, wortmannin or LY294002, blocked the survi val effects of both TX14(A) and IGF-I, In contrast, only TX14(A) anti-apopt otic activity was blocked by the MEK inhbitor, PD98059, although TX14(A) an d IGF-I are potent activators of extracellular regulated kinases in Schwann cells. Phosphorylation of the PI3K signaling target, Akt, was measured; TX 14(A) and IGP-I increased Akt activity by 12-fold and 22-fold, respectively , that was inhibited by LY294002, These findings indicate that prosaposin a nd IGF-I use the PI3K/Akt pathway to induce survival of Schwann cells, (C) 1999 Wiley-Liss, Inc.