Murine protein serine-threonine kinase 38 (MPK38), also known as maternal embryonic leucine zipper kinase (Melk), is a member of the AMP-activated protein kinase (AMPK)-related kinase family and regulates multiple cellular processes, including cell cycle, stem cell self-renewal, apoptosis, carcinogenesis, and metabolism, and is activated in response to apoptosis signal-regulating kinase 1 (ASK1)/TGF-β/p53 signals. A serine/threonine protein phosphatase PP5 has been suggested to negatively regulate the functions of ASK1 and p53. Here, PP5 is found to be a binding partner of MPK38 in cells. The association of PP5 and MPK38 is mediated via the N-terminal domain of PP5 and the C-terminal domain of MPK38. PP5 dose-dependently suppressed the kinase activity and functions of MPK38, as determined by in vitro kinase assays, reporter assays, and apoptosis assays, by destabilizing MPK38. The inhibitory effect of PP5 on MPK38-dependent ASK1/TGF-β/p53 signaling is also confirmed in MEF cells that were null (-/-) for PP5. Consistently, PP5 overexpression by an adenoviral delivery worsens obesity-associated metabolic disturbances in high fat diet (HFD)-fed C57/BL6 mice. However, such adverse effects are not observed in MPK38-deficient obese mice. These findings suggest that PP5 physiologically functions as a specific inhibitor of MPK38 that may participate in obesity metabolism.
18 - 21 May 2019
European Society of Endocrinology