Genetic deletion of the Pten tumor suppressor gene promotes cell motility by activation of Rac1 and Cdc42 GTPases

Abstract

Pten (Phosphatase and tensin homolog deleted on chromosome 10) is a recently identified tumor suppressor gene which is deleted or mutated in a variety of primary human cancers and in three cancer predisposition syndromes [1]. Pten regulates apoptosis and cell cycle progression through its phosphatase activity on phosphatidylinositol (PI) 3,4,5-trisphosphate (PI(3,4,5)P(3)), a product of PI 3-kinase [2-5]. Pten has also been implicated in controlling cell migration [6], but the exact mechanism is not very clear. Using the isogenic Pten(+/+) and Pten(-/-) mouse fibroblast lines, here we show that Pten deficiency led to increased cell motility. Reintroducing the wild-type Pten, but not the catalytically inactive Pten C124S or lipid-phosphatase-deficient Pten G129E mutant, reduced the enhanced cell motility of Pten-deficient cells. Moreover, phosphorylation of the focal adhesion kinase p125(FAK) was not changed in Pten(-/-) cells. Instead, significant increases in the endogenous activities of Rac1 and Cdc42, two small GTPases involved in regulating the actin cytoskeleton [7], were observed in Pten(-/-) cells. Overexpression of dominant-negative mutant forms of Rac1 and Cdc42 reversed the cell migration phenotype of Pten(-/-) cells. Thus, our studies suggest that Pten negatively controls cell motility through its lipid phosphatase activity by down-regulating Rac1 and Cdc42.

PTEN expression is associated with prognosis for patients with advanced endometrial carcinoma undergoing postoperative chemotherapy

“…16 Indeed, PTEN deficiency led to increased cell motility in PTEN -/-fibroblasts and reintroducing the PTEN gene reduced the enhanced motility of the cells. 17 PTEN inactivation may lead to a more aggressive and metastatic phenotype and may be directly involved in the progression of endometrial carcinoma.…”

The Akt pathway in human breast cancer: a tissue-array-based analysis

“…This activity has been shown to occur independent of Akt. 26,27 Thus, it may be hypothesized that, in breast cancer, PTEN loss activates the Rho family proteins, leading to increased cell migration and invasion through pathways independent of Akt. Further studies are needed for confirmation.…”

PTEN signaling in brain: neuropathology and tumorigenesis

“…Pten deletion in early neural precursors in vivo caused profound neuronal migration defects (Backman et al, 2001;Kwon et al, 2001;Marino et al, 2002;Fraser et al, 2004;Yue et al, 2005). In mammalian fibroblasts, Pten influences migration by regulation of Rac1 and Cdc42 in a lipid phosphatase-dependent manner (Liliental et al, 2000). However, many studies suggest that the effects of PTEN on migration are independent of lipid phosphatase activity, with one study indicating that the C2 domain was required (Raftopoulou et al, 2004) and another implicating the protein phosphatase activity of PTEN (Leslie et al, 2007).…”

“…It is possible that the effects of PTEN on cell migration in vitro are dependent on experimental conditions. Indeed, studies suggesting that the lipid phosphatase activity of PTEN regulates migration by RAC1 inhibition were performed on fibronectin and mediated by a 5 b 1 integrin (Liliental et al, 2000); however, Dey et al (2008) studied glioma cell migration on vitronectin, which binds a v b 3 integrin, and showed that PTEN's protein phosphatase activity negatively regulated RAC1 indirectly by regulating the activity of the SRC-family kinase, FYN. It has also been suggested that PTEN may regulate cell migration by directly dephosphorylating FAK in the DBTRG-05MG glioblastoma cell line (Tamura et al, 1998); however, other studies have shown that PTEN does not influence FAK phosphorylation in other cell lines (Maier et al, 1999;Jones et al, 2001).…”