PHLPPing through history: a decade in the life of PHLPP phosphatases

Abstract

In the decade since their discovery, the PH domain Leucine rich repeat Protein Phosphatases (PHLPP) have emerged as critical regulators of cellular homeostasis and their dysregulation is associated with various pathophysiologies, ranging from cancer to degenerative diseases such as diabetes and heart disease. The two PHLPP isozymes, PHLPP1 and PHLPP2, were identified in a search for phosphatases that dephosphorylate Akt, and thus suppress growth factor signaling. However, given that there are over 200,000 phosphorylated residues in a single cell, and fewer than 50 Ser/Thr protein phosphatases, it is not surprising that PHLPP has many other cellular functions yet to be discovered, including a recently identified role in regulating the epigenome. Both PHLPP1 and PHLPP2 are commonly deleted in human cancers, supporting a tumor suppressive role. Conversely, the levels of one isozyme, PHLPP1, are elevated in diabetes. Thus, mechanisms to correctly control PHLPP activity in cells are critical for normal cellular homeostasis. This review summarizes the known functions of PHLPP and its role in disease.

Cannabinoid‐1 Receptor Antagonism Improves Glycemic Control and Increases Energy Expenditure Through Sirtuin‐1/Mechanistic Target of Rapamycin Complex 2 and 5′Adenosine Monophosphate–Activated Protein Kinase Signaling

“…We have earlier demonstrated that the Pleckstrin homology domain and leucine‐rich repeat protein phosphatase 1 (PHLPP1), which directly dephosphorylates and inactivates Akt‐2, is a downstream target of CB 1 R for inducing insulin resistance in DIO mice . mTORC2 and PHLPP1 have been recently identified as part of a regulatory complex for chaperone‐mediated autophagy where they serve opposite—stimulatory and inhibitory—functions .…”

PHLPP2 as a novel metastatic and prognostic biomarker in non‐small cell lung cancer patients

“…As an identified tumor suppressive gene, multiple lines of evidence reveal the role of PHLPP2 in tumor progression . PHLPP2 is involved in the inhibition of malignant behaviors of cancer attributed to the suppression of prosurvival signaling such as through the PI3K/Akt signaling pathway . In addition, PHLPP2 can dephosphorylate and stabilize the Myc oncogene to suppress the progression of prostate cancer .…”

“…PHLPP2 regulates several cellular pathways in cancer . Notably, direct dephosphorylation by PHLPP2 inactivates pro‐oncogenic AGC kinases such as Akt, S6K, and PKC and activates pro‐apoptotic kinases such as Mst1 .…”

“…The essential role of PHLPP2 in promoting the autophagic degradation of MMP2 protein and bladder cancer invasion was recently identified . In reference to NSCLC, studies of the tumor suppressive effects and functional mechanisms of PHLPP2 are ongoing . PHLPP2 downregulation was reported to promote lung carcinogenesis by inducing inflammatory tumor necrosis factor alpha (TNFα) .…”

MiR-135a Protects Vascular Endothelial Cells Against Ventilator-Induced Lung Injury by Inhibiting PHLPP2 to Activate PI3K/Akt Pathway

“…In addition, studies indicate that PHLPP1 and PHLPP2 may both serve as tumor suppressors, largely attributed to PHLPP-dependent suppression of pro-survival signaling, such as through the PI3K/ Akt signaling pathway [37,46]. The phosphatidylinositol-3 kinase (PI3K) signaling pathway plays an essential role in some physiological and cellular processes including cell proliferation, growth, survival, migration, and metabolism [47].…”