Opposite roles of FAP-1 and dynamin in the regulation of Fas (CD95) translocation to the cell surface and susceptibility to Fas ligand-mediated apoptosis

doi:10.1074/jbc.M509866200

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Papers In Press, published online ahead of print November 23, 2005
J. Biol. Chem, 10.1074/jbc.M509866200
Submitted on September 7, 2005
Accepted on November 23, 2005

Opposite roles of FAP-1 and dynamin in the regulation of Fas (CD95) translocation to the cell surface and susceptibility to Fas ligand-mediated apoptosis

Vladimir N. Ivanov, Ze'ev Ronai, and Tom K. Hei

Center for Radiological Research, Columbia University College of Physicians and Surgeons, New York, NY 10032

Corresponding Author: vni3{at}columbia.edu

Human melanoma is the most aggressive form of skin cancer and is extremely resistant to radiation and chemotherapy. One of the critical parameters of this resistance is downregulation of Fas (CD95) cell surface expression. Using TIG3 normal human fibroblasts and human melanoma cell lines, we investigated transcriptional regulation of FAP-1, a regulator of Fas translocation in the cell. Protein tyrosine phosphatase FAP-1 (PTPN13, PTP-BAS) interacts with human Fas protein and prevents its export from the cytoplasm to the cell surface. In contrast, dynamin-2 facilitates Fas protein translocation from the Golgi apparatus via the trans-Golgi network to the cell surface. Suppression of dynamin functions by dominant negative dynamin K44A blocks Fas export, whereas the downregulation of FAP-1 expression by specific RNAi restores Fas export (a phenomenon which could still be downregulated in the presence of dominant-negative dynamin). Based on the FAP-1- and dynamin-dependent regulation of Fas translocation, we have created human melanoma lines with different levels of surface expression of Fas. Treatment of these melanoma lines with soluble Fas Ligand resulted in programmed cell death that was proportional to the preexisting levels of surface Fas. Taking into consideration the well-known observations that FAP-1 expression is often up-regulated in metastatic tumors, we have established a causal connection between high basal NF- $kappa$ B transcription factor activity (which is a hallmark of many types of metastatic tumors) and NF- $kappa$ B-dependent transcriptional regulation of FAP-1 gene expression that finally restricts Fas protein trafficking, thereby, facilitating the survival of cancer cells.

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