Moesin-ezrin-radixin-like protein (merlin) mediates protein interacting with the carboxyl terminus-1 (PICT-1)-induced growth inhibition of glioblastoma cells in the nucleus

Hongbo Chen, Lin Mei, Lanzhen Zhou, Xudong Zhang, Caiping Guo, Junchang Li, Huixia Wang, Yongqiang Zhu, Yi Zheng, Laiqiang Huang
International Journal of Biochemistry & Cell Biology 2011, 43 (4): 545-55
Moesin-ezrin-radixin-like protein (merlin) has long been considered a unique tumour suppressor that inhibits mitogenic signalling only at the membrane-cytoskeleton interface. However, the nucleocytoplasmic shuttling of merlin in a cell cycle-dependent manner has recently been observed, indicating that merlin may also exert its tumour-suppressive activity by interacting with specific nuclear protein partners. We have identified protein interacting with carboxyl terminus 1 (PICT-1) as a novel merlin-binding partner. Although the detailed mechanisms are not fully understood, several lines of evidence have previously implicated PICT-1 as a candidate tumour suppressor, including its phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-dependent growth-suppression and cell-killing activities. We show here that PICT-1 is localised to the nucleolus, and Ser518-dephosphorylated merlin (the growth-inhibitory form of merlin) can interact with PICT-1 in the nucleolus. Ectopic expression of PICT-1, both in PTEN-positive HeLa cells and in PTEN-deficient U251 cells, effectively represses cyclin D1 expression, arrests the cell cycle at G0/G1, and promotes cell apoptosis. PICT-1 (1-356), a carboxyl-terminus truncated mutant that has lost the ability to bind merlin, has a markedly reduced inhibitory effect on the cell cycle and proliferation. Knockdown of merlin expression by siRNA attenuates the inhibitory effects induced by PICT-1 over-expression. We propose that merlin mediates PICT-1-induced growth inhibition by translocating to the nucleolus and binding PICT-1.

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