Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner

He, Kunyan; Jang, Sung-Wuk; Joshi, Jayashree; Yoo, Min-Heui; Ye, Keqiang

doi:10.1091/mbc.e10-11-0923

Cited by 33 publications

(34 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PIKE-A is a downstream effector of various hormones, including prolactin, insulin, and netrin-1 (22,24,40,41). In this report, we further demonstrate that PIKE-A is a new player in TNF-α signaling to control muscular energy metabolism.…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor-α Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle

et al. 2017

Self Cite

View full text Add to dashboard Cite

Tumor necrosis factor-α (TNF-α) is an inflammatory cytokine that plays a central role in obesity-induced insulin resistance. It also controls cellular lipid metabolism, but the underlining mechanism is poorly understood. We report in this study that phosphoinositide 3-kinase enhancer A (PIKE-A) is a novel effector of TNF-α to facilitate its metabolic modulation in the skeletal muscle. Depletion of PIKE-A in C2C12 myotubes diminished the inhibitory activities of TNF-α on mitochondrial respiration and lipid oxidation, whereas PIKE-A overexpression exacerbated these cellular responses. We also found that TNF-α promoted the interaction between PIKE-A and AMP-activated protein kinase (AMPK) to suppress its kinase activity in vitro and in vivo. As a result, animals with PIKE ablation in the skeletal muscle per se display an upregulation of AMPK phosphorylation and a higher preference to use lipid as the energy production substrate under high-fat diet feeding, which mitigates the development of diet-induced hyperlipidemia, ectopic lipid accumulation, and muscle insulin resistance. Hence, our data reveal PIKE-A as a new signaling factor that is important for TNF-α–initiated metabolic changes in skeletal muscle.

show abstract

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor-α Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the presence of netrin-1, the multimerized receptors recruit different adapter proteins and activate PI3K/Akt, ERK1/2, and small GTPase RhoA/Rac-1/Cdc-42 to affect cell survival, motility, invasion, and morphogenesis through cytoskeletal rearrangements (22)(23)(24). It is reported that PP1A acts downstream of RhoA in LPA-induced YAP dephosphoryaltion (25) and PI3K and ERK1/2 signaling is involved in the regulation of PP1A activity in cancer cells (26,27).…”

Section: Discussionmentioning

confidence: 99%

Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability

Luo

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Yes-associated protein (YAP), a transcription coactivator, is the major downstream effector of the Hippo pathway, which plays a critical role in organ size control and cancer development. However, how YAP is regulated by extracellular stimuli in tumorigenesis remains incompletely understood. Netrin-1, a laminin-related secreted protein, displays proto-oncogenic activity in cancers. Nonetheless, the downstream signaling mediating its oncogenic effects is not well defined.Here we show that netrin-1 via its transmembrane receptors, deleted in colorectal cancer and uncoordinated-5 homolog, up-regulates YAP expression, escalating YAP levels in the nucleus and promoting cancer cell proliferation and migration. Inactivating netrin-1, deleted in colorectal cancer, or uncoordinated-5 homolog B (UNC5B) decreases YAP protein levels, abrogating cancer cell progression by netrin-1, whereas knockdown of mammalian STE20-like protein kinase 1/2 (MST1/2) or large tumor suppressor kinase 1/2 (Lats1/2), two sets of upstream core kinases of the Hippo pathway, has no effect in blocking netrin-1-induced up-regulation of YAP. Netrin-1 stimulates phosphatase 1A to dephosphorylate YAP, which leads to decreased ubiquitination and degradation, enhancing YAP accumulation and signaling. Hence, our findings support that netrin-1 exerts oncogenic activity through YAP signaling, providing a mechanism coupling extracellular signals to the nuclear YAP oncogene.netrin-1 | YAP | cancer progression

show abstract

“…It has also demonstrated that PIKE-A associates with UNC5B in glioblastoma cell lines 39 . The PIKE-A/UNC5B binding is tightly regulated by Akt, in which Akt-induced phosphorylation of PIKE-A on Ser-472 promotes its interaction with UNC5B.…”

Section: Functions Of Pike In Tumorigenesismentioning

confidence: 97%

“…As such, netrin-1 might stimulate Akt activation, which subsequently phosphorylates PIKE-A, escalating its binding to UNC5B, and thereby inhibiting the receptor cleavage and apoptosis-inducing activity. In addition, PIKE-A (S472) phosphorylation feed backs positively to further elevate the Akt activity and leads to p53 degradation through the Akt-MDM2 pathway, resulting in down-regulation of UNC5B 39 . Since PIKE-L associates with DCC in the brain, conceivably, other PIKE isoforms may interact with DCC and demonstrate a potential function in tumorigenesis.…”

Section: Functions Of Pike In Tumorigenesismentioning

confidence: 99%

The roles of PIKE in tumorigenesis

2013

Acta Pharmacol Sin

Self Cite

View full text Add to dashboard Cite

Tumorigenesis is the process by which normal cells evolve the capacity to evade and overcome the constraints usually placed upon their growth and survival. To ensure the integrity of organs and tissues, the balance of cell proliferation and cell death is tightly maintained. The proteins controlling this balance are either considered oncogenes, which promote tumorigenesis, or tumor suppressors, which prevent tumorigenesis. Phosphoinositide 3-kinase enhancer (PIKE) is a family of GTP-binding proteins that possess anti-apoptotic functions and play an important role in the central nervous system. Notably, accumulating evidence suggests that PIKE is a proto-oncogene involved in tumor progression. The PIKE gene (CENTG1) is amplified in a variety of human cancers, leading to the resistance against apoptosis and the enhancement of invasion. In this review, we will summarize the functions of PIKE proteins in tumorigenesis and discuss their potential implications in cancer therapy.

show abstract

Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner

Cited by 33 publications

References 29 publications

Tumor Necrosis Factor-α Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle

Tumor Necrosis Factor-α Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle

Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability

The roles of PIKE in tumorigenesis

Contact Info

Product

Resources

About