Structural Biochemistry/Phosphatase PHLPP

The life cycle of protein kinase C is regulated by multiple phosphorylation as well as dephosphorylation. The maturation of protein kinase C involves three ordered phosphorylations. These phosphorylations are: 1) One at the activation loop, 2) COOH-terminal sites, but two of them. These processes lead to a signaling-competent enzyme. The process of dephosphorylation results in protein degradation.

Recent discoveries have illustrated a new family of protein phosphatases called PHLPP, which stands for “PH domain leucine-rich repeat protein phosphatase”. PHLPP terminates Protein Kinase B signaling through dephosphorylation of the hydrophobic motif on Protein Kinase B also known as Akt.

There are two isoforms of PHLPP called PHLPP1 and PHLPP2, which dephosphorylate the hydrophobic motif on PKC BII. This process brings Protein Kinase C to the detergent-insoluble fraction, which effectively terminates its life cycle.

Deletion mutagenesis elucidates the idea that PH domain is vital for the effective dephosphorylation of PKC BII by PHLPP in cells. However, for the PDZ-binding motif, which is necessary for Akt regulation, it is dispensable.

The depletion of PHLPP in colon cancer and normal breast epithelial cells results in an increase in conventional and novel PKC levels, revealing that PHLPP regulates the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif. This also causes the destabilization of the enzyme, which promotes its degradation.

Protein phosphorylation acts as one of the most significant regulatory mechanisms in cell signaling. Vital cellular decisions such as death or survival and proliferation or differentiation are made depending on the phosphorylation state of the signaling molecules. Therefore, precise control of the balance between phosphorylation and dephosphorylation is crucial for living organisms to maintain normal physiological functions. The disturbance of regulation of the signaling pathways, which results in disturbing a sense of equilibrium leads to the development of diseases such as cancer and diabetes. This leads to a pathogenic state in which both kinases and phosphatase are identified as oncogenes or tumor suppressors.

References: The Phosphatase PHLPP Controls the Cellular Levels of Protein Kinase C; By: Tianyan Gao, John Brognard, and Alexandra Newton from the Department of Pharmacology and the Biomedical Sciences Graduate Program, University of California, San Diego