X-linked inhibitor of apoptosis protein negatively regulates neuronal differentiation through interaction with cRAF and Trk.
X-linked Inhibitor of apoptosis protein (XIAP) has been classically identified as a cell death regulator. Here, we demonstrate a novel function of XIAP as a regulator of neurite outgrowth in neuronal cells. In PC12 cells, XIAP overexpression prevents NGF-induced neuronal differentiation, whereas NGF treatment induces a reduction of endogenous XIAP levels concomitant with the induction of neuronal differentiation. Accordingly, downregulation of endogenous XIAP protein levels strongly increases neurite outgrowth in PC12 cells as well as axonal and dendritic length in primary cortical neurons. The effects of XIAP are mediated by the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinases (ERKs) pathway since blocking this pathway completely prevents the neuritogenesis mediated by XIAP downregulation. In addition, we found that XIAP binds to cRaf and Trk receptors. Our results demonstrate that XIAP plays a new role as a negative regulator of neurotrophin-induced neurite outgrowth and neuronal differentiation in developing neurons.
Institut de Neurociències and Dpt. Bioquímica and Biología Molecular, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain.
Rut
R
Fadó
Rana S
RS
Moubarak
Alfredo J
AJ
Miñano-Molina
Bruna
B
Barneda-Zahonero
Jorge
J
Valero
Carlos A
CA
Saura
Julio
J
Moran
Joan X
JX
Comella
José
J
Rodríguez-Álvarez
D000818:Animals; D002454:Cell Differentiation; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
D051636:X-Linked Inhibitor of Apoptosis Protein; D020917:Receptor, trkA; D019908:Proto-Oncogene Proteins c-raf