PHLPP2

Last update 08 May 2025

Basic Info

Synonyms

KIAA0931, PH domain and leucine rich repeat protein phosphatase 2, PH domain leucine-rich repeat-containing protein phosphatase 2

+ [5]

Introduction

Protein phosphatase involved in regulation of Akt and PKC signaling. Mediates dephosphorylation in the C-terminal domain hydrophobic motif of members of the AGC Ser/Thr protein kinase family; specifically acts on 'Ser-473' of AKT1, 'Ser-660' of PRKCB isoform beta-II and 'Ser-657' of PRKCA. Akt regulates the balance between cell survival and apoptosis through a cascade that primarily alters the function of transcription factors that regulate pro- and antiapoptotic genes. Dephosphorylation of 'Ser-473' of Akt triggers apoptosis and decreases cell proliferation. Also controls the phosphorylation of AKT3. Dephosphorylates STK4 on 'Thr-387' leading to STK4 activation and apoptosis (PubMed:20513427). Dephosphorylates RPS6KB1 and is involved in regulation of cap-dependent translation (PubMed:21986499). Inhibits cancer cell proliferation and may act as a tumor suppressor. Dephosphorylation of PRKCA and PRKCB leads to their destabilization and degradation. Dephosphorylates RAF1 inhibiting its kinase activity (PubMed:24530606).

100 Clinical Results associated with PHLPP2

100 Translational Medicine associated with PHLPP2

0 Patents (Medical) associated with PHLPP2

196

Literatures (Medical) associated with PHLPP2

01 May 2025·Toxicology and Applied Pharmacology

Methyltransferase-like enzyme 14 exacerbates retinal ganglion cell damage and diabetic retinopathy through N6-methyladenosine-dependent upregulation of pleckstrin homology domain and leucine rich repeat protein phosphatase 2

Article

Author: Chen, Li ; Liu, Xuan ; Wei, Ting ; Hu, Conghui ; Quan, Yumeng ; Cui, Lijun

N6-methyladenosine (m6A) modification of pleckstrin homology domain and leucine rich repeat protein phosphatase 2 (PHLPP2), mediated by methyltransferase-like enzyme 14 (METTL14), plays a critical role in regulating PHLPP2 expression across various pathological conditions. This study aims to ascertain whether METTL14 influences m6A methylation of PHLPP2 in diabetic retinopathy (DR) and to delineate the precise function of the METTL14/PHLPP2 axis in disease progression. METTL14 levels were observed to be elevated in retinas of DR rats and in HG-stimulated RGCs, coinciding with an increase in PHLPP2 m6A modification. Knockdown of METTL14 resulted in significant reductions in PHLPP2 expression and its m6A modification. Silencing METTL14 mitigated HG-induced damage in RGCs, which was linked to the inhibition of apoptosis, oxidative stress and inflammation. This protective effect could be negated through the restoration of PHLPP2. METTL14 knockdown modulated the AKT/GSK-3β/Nrf2 signal cascade through PHLPP2. Silencing METTL14 resulted in the downregulation of METTL14 and PHLPP2 in the retinas of DR rats, ameliorated visual function impairment and reduced the pathological alterations. These protective effects of METTL14 silencing against DR were also weakened when PHLPP2 was restored. Overall, these results suggest that suppressing METTL14 improves HG-induced damage in RGCs and protects against DR by downregulating PHLPP2 through m6A modification.

08 Apr 2025·Proceedings of the National Academy of Sciences

PHLPP2 is a pseudophosphatase that lost activity in the metazoan ancestor

Article

Author: Grishkovskaya, Irina ; Cerron-Alvan, Luis M. ; Ogris, Egon ; Wenzl, Karoline ; Leonard, Thomas A. ; Žagrović, Bojan ; Truebestein, Linda ; Meier, Vanessa ; Miočić-Stošić, Fran ; Haselbach, David ; Kircheva, Nikoleta ; Antonioli, Sumire ; Brandstätter, Andreas ; Veis, Jiri ; Bock, Christoph ; Dudev, Todor ; Hartl, Markus ; Angelova, Silvia E. ; Husremović, Tarik ; Irwin, Nicholas A. T. ; Piëch, Lucas ; Hann, Stephan ; Anrather, Dorothea ; Leeb, Martin ; Siess, Katharina M.

The phosphoinositide 3-kinase (PI3K) pathway is a major regulator of cell and organismal growth. Consequently, hyperactivation of PI3K and its downstream effector kinase, Akt, is observed in many human cancers. Pleckstrin homology domain leucine-rich repeat-containing protein phosphatases (PHLPP), two paralogous members of the metal-dependent protein phosphatase family, have been reported as negative regulators of Akt signaling and, therefore, tumor suppressors. However, the stoichiometry and identity of the bound metal ion(s), mechanism of action, and enzymatic specificity of these proteins are not known. Seeking to fill these gaps in our understanding of PHLPP biology, we unexpectedly found that PHLPP2 has no catalytic activity in vitro. Instead, we found that PHLPP2 is a pseudophosphatase with a single zinc ion bound in its catalytic center. Furthermore, we found that cancer genomics data do not support the proposed role of PHLPP1 or PHLPP2 as tumor suppressors. Phylogenetic analyses revealed an ancestral phosphatase that arose more than 1,000 Mya, but that lost activity at the base of the metazoan lineage. Surface conservation indicates that while PHLPP2 has lost catalytic activity, it may have retained substrate binding. Finally, using phylogenomics, we identify coevolving genes consistent with a scaffolding role for PHLPP2 on membranes. In summary, our results provide a molecular explanation for the inconclusive results that have hampered research on PHLPP and argue for a focus on the noncatalytic roles of PHLPP1 and PHLPP2.

01 Mar 2025·Osteoarthritis and Cartilage Open

Postnatal deletion of Phlpp1 in chondrocytes delays post-traumatic osteoarthritis in male mice

Article

Author: Peralta-Herrera, Eduardo ; Weaver, Samantha R ; Zars, Elizabeth L ; Bradley, Elizabeth W ; Oviedo, Manuela ; Arnold, Katherine M ; Westendorf, Jennifer J

ObjectiveOsteoarthritis is a chronic, debilitating disease that causes long-term pain and immobility. Germline deletion of Phlpp1 or administration of small molecules that inhibit Phlpp1 prevents post-traumatic osteoarthritis (PTOA) in mice. However, the chondrocyte-intrinsic role of Phlpp1 in PTOA progression is unknown. The objective of this study was to determine how postnatal, chondrocyte-directed deletion of Phlpp1 affects PTOA progression in the presence or absence of Phlpp inhibitors.DesignPhlpp1^fl/fl; Agc-Cre^ERT2 and Agc-Cre^ERT2 mice were injected with tamoxifen at 12 weeks of age to generate Phlpp1-CKO_AgcERT and control (AgcERT) groups. Male mice underwent surgery to destabilize the medial meniscus (DMM) at 17 weeks of age. A separate cohort of male Phlpp1-CKO_AgcERT mice were administered an intra-articular injection of NSC117079, a Phlpp1/2 inhibitor, or saline seven weeks after DMM surgery. Activity and mechanical allodynia were monitored throughout the experiment and cartilage damage was evaluated 12 weeks post-surgery.ResultsPhlpp1-CKO_AgcERT mice had less cartilage damage than AgcERT littermates 12 weeks after DMM surgery but exhibited no differences in activity. Prg4 expression was also higher in articular chondrocytes of Phlpp1-CKO_AgcERT mice. Intra-articular administration of NSC117079 to Phlpp1-CKO_AgcERT mice improved cartilage structure, subchondral bone sclerosis, and mechanical allodynia at 12 weeks post-DMM.ConclusionsPostnatal deletion of Phlpp1 in chondrocytes attenuates DMM-induced cartilage damage and subchondral bone sclerosis but does not prevent pain-related behaviors. Intra-articular injection of Phlpp inhibitors delays mechanical allodynia in Phlpp1-CKO_AgcERT mice. These data indicate that Phlpp1 in chondrocytes affects articular cartilage structure after injury, but pain-related behaviors are controlled by Phlpp1 or Phlpp2 in other cell types.

Analysis

Perform a panoramic analysis of this field.

view full example data

AI Agents Built for Biopharma Breakthroughs

Accelerate discovery. Empower decisions. Transform outcomes.

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

PHLPP2

Basic Info

Related

Analysis