Fyn-phosphorylated PIKE-A binds and inhibits AMPK signaling, blocking its tumor suppressive activity.

Abstract

The AMP-activated protein kinase, a key regulator of energy homeostasis, has a critical role in metabolic disorders and cancers. AMPK is mainly regulated by cellular AMP and phosphorylation by upstream kinases. Here, we show that PIKE-A binds to AMPK and blocks its tumor suppressive actions, which are mediated by tyrosine kinase Fyn. PIKE-A directly interacts with AMPK catalytic alpha subunit and impairs T172 phosphorylation, leading to repression of its kinase activity on the downstream targets. Mutation of Fyn phosphorylation sites on PIKE-A, depletion of Fyn, or pharmacological inhibition of Fyn blunts the association between PIKE-A and AMPK, resulting in loss of its inhibitory effect on AMPK. Cell proliferation and oncogenic assays demonstrate that PIKE-A antagonizes tumor suppressive actions of AMPK. In human glioblastoma samples, PIKE-A expression inversely correlates with the p-AMPK levels, supporting that PIKE-A negatively regulates AMPK activity in cancers. Thus, our findings provide additional layer of molecular regulation of the AMPK signaling pathway in cancer progression.

• Authors: S Zhang, Q Qi, C B Chan, W Zhou, J Chen, H R Luo, C Appin, D J Brat, K Ye
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 23 Issue 1 Pg. 52-63 (Jan 2016) ISSN: 1476-5403 [Electronic] England
• PMID: 26001218 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• GTPase-Activating Proteins
• Tumor Suppressor Proteins
• FYN protein, human
• Proto-Oncogene Proteins c-fyn
• Protein Serine-Threonine Kinases
• STK11 protein, human
• AMP-Activated Protein Kinase Kinases
• AMP-Activated Protein Kinases
• AGAP2 protein, human
• GTP-Binding Proteins

Topics

• AMP-Activated Protein Kinase Kinases
• AMP-Activated Protein Kinases (genetics, metabolism)
• GTP-Binding Proteins (genetics, metabolism)
• GTPase-Activating Proteins (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Glioblastoma (genetics, metabolism, pathology)
• HEK293 Cells
• Humans
• Phosphorylation
• Protein Binding
• Protein Serine-Threonine Kinases (genetics)
• Proto-Oncogene Proteins c-fyn (genetics, metabolism)
• Signal Transduction (genetics)
• Tumor Suppressor Proteins (genetics, metabolism)