p70S6K1 (S6K1)-mediated Phosphorylation Regulates Phosphatidylinositol 4-Phosphate 5-Kinase Type I γ Degradation and Cell Invasion

Abstract

Edited by Alex TokerPhosphatidylinositol 4-phosphate 5-kinase type I ␥ (PIPKI␥90) ubiquitination and subsequent degradation regulate focal adhesion assembly, cell migration, and invasion. However, it is unknown how upstream signals control PIPKI␥90 ubiquitination or degradation. Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKI␥90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKI␥90 phosphorylation is essential for cell migration and invasion. Moreover, PIPKI␥90 phosphorylation is required for the development of focal adhesions and invadopodia, key machineries for cell migration and invasion. Surprisingly, substitution of Thr-553 and Ser-555 with Ala promoted PIPKI␥90 ubiquitination but enhanced the stability of PIPKI␥90, and depletion of S6K1 also enhanced the stability of PIPKI␥90, indicating that PIPKI␥90 ubiquitination alone is insufficient for its degradation. These data suggest that S6K1-mediated PIPKI␥90 phosphorylation regulates cell migration and invasion by controlling PIPKI␥90 degradation.Cell migration and invasion are prerequisites for cancer metastasis (1, 2). Thus, the elucidation of the molecular mechanisms of cell migration and invasion is a compelling goal in cancer cell biology.Phosphatidylinositol 4 phosphate 5-kinase type I ␥ (PIPKI␥90) 2 binds talin and localizes to focal adhesions (FAs) (3, 4). It catalyzes ATP-dependent phosphorylation of phosphatidylinositol 4-phosphate (PIP) to generate phosphatidylinositol 4,5-bisphosphate (PIP 2 ), which binds and activates talin, vinculin, and focal adhesion kinase to mediate FA assembly (5, 6). PIP 2 also binds many cytoskeletal proteins, such as neural Wiskott-Aldrich Syndrome protein, gelsolin, and profilin, to regulate actin polymerization (7-10).In addition, PIP 2 is a precursor of several lipid second messengers, such as phosphatidylinositol 3,4,5-triphosphate (PIP 3 ), inositol 1,4,5-triphosphate, and diacylglycerol. We have shown that depletion of PIPKI␥90 completely abolishes PIP 3 production in HCT119 human colon cancer cells (11), indicating a critical role of PIPKI␥90 in lipid signaling. PIPKI␥90 is necessary for epithelial cell adherens junction assembly and progression through the E-cadherin-␤-catenin signal pathway (12). PIPKI␥90 depletion inhibits cell proliferation, MMP9 secretion, and cell motility (13,14). PIPKI␥90 is essential for cell migration, invasion, and metastasis. It is required for focal adhesion assembly and disassembly, key steps in cell migration (11). Depletion of PIPKI␥90 inhibits growth factor-stimulated cell migration in MDA-MB-231 breast cancer cells and HeLa cervical cancer cells (14, 15). PIPKI␥90 knockdown also blocks the invasion of breast cancer and colon cancer cells (11, 16). Furthermore, PIPKI␥90-depleted 4T1 breast cancer cells show significant reduction in tumor progression and metastasis (13). PIPKI␥90 also regulates neutrophil migration by controlling cell polarity as well as rear retraction (17)(18)(19). PIPKI␥90 is a substrate for ...

CircZNF609 promotes breast cancer cell growth, migration, and invasion by elevating p70S6K1 via sponging miR-145-5p

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The role of talin2 in breast cancer tumorigenesis and metastasis

“…To examine the possible association of talin2 with breast cancer progression, human breast cancer tissue array slides, including 17 cases of ductal carcinoma in situ (DCIS), 32 cases of invasive ductal carcinoma (IDC) and 30 cases of tumor adjacent tissues, were stained for talin2. Immunohistochemical staining was performed as we described previously [ 29 ]. Talin2 staining was significantly higher in DCIS and IDC tissues than the staining in the adjacent tissues ( P < 0.001), and talin2 staining was also higher in IDC tissues than DCIS tissues ( P < 0.001; Figure 6C ).…”

ASC amino acid transporter 2, defined by enzyme‐mediated activation of radical sources, enhances malignancy of GD2‐positive small‐cell lung cancer

“…[38][39][40] Moreover, p70 S6K1-mediated phosphorylation controls phosphatidylinositol 4-phosphate 5-kinase type I degradation to regulate development of focal adhesions and invadopodia, and consequently, cell migration and invasion. 41 In this study, GPNA decreased glutamine uptake by ASCT2 in SK-LC-17…”