Rak Functions as a Tumor Suppressor by Regulating PTEN Protein Stability and Function

Abstract

Summary Expression of PTEN tumor suppressor is frequently lost in breast cancer in the absence of mutation or promoter methylation through as yet undetermined mechanisms. In this study, we demonstrated that the Rak tyrosine kinase physically interacts with PTEN and phosphorylates PTEN on Tyr 336. The knockdown of Rak enhanced the binding of PTEN to its E3 ligase, NEDD4-1, and promoted PTEN polyubiquitination, leading to PTEN protein degradation. Notably, ectopic expression of Rak effectively suppressed breast cancer cell proliferation, invasion, and colony formation in vitro and tumor growth in vivo. Furthermore, Rak knockdown was sufficient to transform normal mammary epithelial cells. Therefore, Rak acts as a bona fide tumor suppressor gene through the mechanism of regulating PTEN protein stability and function.

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…RAK is a tyrosine kinase and may phosphorylate PTEN directly at Y336. 61 The function of these proteins may be lost in certain tumors and inhibition of their expression has been associated with tumorigenicity. 62,63 Other proteins interact with PTEN and inhibit its activity.…”

Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240

“…However, from these studies, it is unclear as to whether the observed effects on PTEN function are attributable to its tyrosine phosphorylation or whether they are mediated indirectly through the phosphorylation of other SRC substrates. Recently, the RAK nonreceptor tyrosine kinase has been shown to enhance PTEN tumor suppressor function by phosphorylating tyrosine 336, thus preventing its degradation by the proteasome (15). This finding highlights the importance of accurately mapping the specific PTEN tyrosine residues phosphorylated in vivo and determining whether they have any role in clinical behavior or as predictors of relapse or indicators of prognosis.…”

“…S6). These data suggest that FGFRs are highly specific Y240 kinases that may modulate PTEN function primarily through phosphorylation at this site, in contrast to SFKs, which regulate PTEN in a number of ways, presumably as a result of their ability to target multiple sites (13)(14)(15). Although PTEN has been shown to interact with platelet-derived growth factor receptors (PDGFRs) (22,23), which are closely related to FGFRs, neither PDGFRα nor EGFR drove robust phosphorylation of Y240 in our in vitro assays (SI Appendix, Fig.…”

“…Tyrosine phosphorylation of PTEN by SRC-family kinases (SFKs) has been proposed to modulate its function in a number of ways, including loss of membrane interaction and altered protein stability (12)(13)(14)(15). PTEN function is compromised in cells displaying high SFK activity, and in particular, inhibition of ErbB2-driven SRC activity by trastuzumab allows PTEN to suppress PI3K signaling in breast cancer cell lines (13,14).…”

The functions of tumor suppressor PTEN in innate and adaptive immunity

“…32 Tyr336 phosphorylation is related to PTEN degradation. 33 In addition, Tyr240 and Tyr315 phosphorylation could help to maintain phosphatase function of PTEN. 34,35 Bolduc et al 16 found that upon phosphorylation of the 380-385 Ser/Thr cluster, the PTEN C-terminal modified tail clamps down intramolecularly on the C2 domain, preventing PTEN from binding to the plasma membrane and reducing its catalytic action toward PIP3.…”