FAS associated phosphatase (FAP-1) blocks apoptosis of astrocytomas through dephosphorylation of FAS.
Astrocytomas are the most common primary tumor of the adult human central nervous system. Despite efforts to develop more effective clinical treatment strategies, median survival time for patients with the most severe form of astrocytoma, glioblastoma multiforme (GBM), remains about one year. Astrocytomas are resistant to cytotoxic therapy in general and radiation therapy in particular, greatly limiting treatment options. One reason for this seems to be defects in the pathways controlling apoptosis. We have characterized the role of the tyrosine phosphatase FAP-1 (FAS-associated phosphatase 1) in astrocytomas. Our studies demonstrate that FAP-1 is overexpressed in astrocytomas and this contributes to the resistance of the tumor cells to FAS-mediated apoptosis. We demonstrate that knockdown of FAP-1 by RNA interference leads to increased apoptosis and increased sensitivity of astrocytoma cells to FAS-induced cell death. FAP-1 binds to FAS in a ligand-dependent manner and forms a signaling complex that modulates the ability of astrocytoma cells to undergo FAS ligand (FASL)-mediated cell death. In astrocytoma cells, FASL treatment induces tyrosine phosphorylation of FAS. FAP-1 dephosphorylates phospho-tyrosine 275 in the carboxyl terminus of FAS. This is the first direct evidence that FAS activity can be regulated by reversible phosphorylation and suggests a mechanism for astrocytoma resistance to apoptosis.
Foehr
Erik D
ED
AGY Therapeutics Inc., Drug Discovery, 270 East Grand Avenue, South San Francisco, CA 94080, USA. efoehr@agyinc.com
Lorente
Gustavo
G
Vincent
Valerie
V
Nikolich
Karoly
K
Urfer
Roman
R
D017209:Apoptosis / Q000502:physiology*; D001254:Astrocytoma / Q000473:pathology*; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019014:fas Receptor / Q000378:metabolism*
D012333:RNA, Messenger; D019014:fas Receptor; D054645:Protein Phosphatase 1; C516742:PTPN13 protein, human; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases