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Phosphatidylinositol 3‐kinase and Akt protein kinase mediate IGF‐I‐ and prosaptide‐induced survival in schwann cells
Author(s) -
Campana W. Marie,
Darin Sam J.,
O'Brien John S.
Publication year - 1999
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/(sici)1097-4547(19990801)57:3<332::aid-jnr5>3.0.co;2-0
Subject(s) - protein kinase b , phosphatidylinositol , microbiology and biotechnology , kinase , pi3k/akt/mtor pathway , protein kinase a , mitogen activated protein kinase kinase , biology , chemistry , signal transduction
Withdrawal of trophic factors necessary for Schwann cell survival regulates Schwann cell number during development and after nerve injury. In the present study, we identified signaling pathways involved in Schwann cell survival by prosaposin, prosaptides (peptides incorporating the neurotrophic sequence of prosaposin), and insulinlike growth factor‐I (IGF‐I). When postnatal Schwann cells were placed in low serum medium, cells underwent abrupt shrinkage, condensation of nuclei occurred, and smooth rounded apoptotic bodies appeared. Dose–response studies of cell death, measured by lactate dehydrogenase (LDH) release, demonstrated that both prosaptide TX14(A) and IGF‐I dose dependently reduced cell death in primary Schwann cells. Histone‐associated DNA fragmentation enzyme‐linked immunosorbent assay, showed a 10‐ and 14‐fold increase in apoptosis after 4 and 24 hr in low serum medium, respectively, that was reduced by prosaposin, TX14(A), or IGF‐I. Phosphatidylinositol 3‐kinase (PI3K) inhibitors, wortmannin or LY294002, blocked the survival effects of both TX14(A) and IGF‐I. In contrast, only TX14(A) anti‐apoptotic activity was blocked by the MEK inhbitor, PD98059, although TX14(A) and IGF‐I are potent activators of extracellular regulated kinases in Schwann cells. Phosphorylation of the PI3K signaling target, Akt, was measured; TX14(A) and IGF‐I increased Akt activity by 12‐fold and 22‐fold, respectively, that was inhibited by LY294002. These findings indicate that prosaposin and IGF‐I use the PI3K/Akt pathway to induce survival of Schwann cells. J. Neurosci. Res. 57:332–341, 1999. © 1999 Wiley‐Liss, Inc.