Protein phosphatase magnesium dependent 1A (PPM1A) regulates the interplay between inflamation and angiogenesis through p38 dephosphrylation

Sara Lavi ¹ Zeev Dvashi ¹ Hadas Jacobi ¹ Meytal Shohat ¹ Daniella Ben-Meir ¹ Shiran Ferber ² Ronit Satchi-Fainaro ² Ruth Ashery-Padan ³ Mordechai Rosner ⁴ Arieh Solomon ⁴

¹Cell Research and Immunology, Faculty of Life Science, Tel Aviv University, Tel Aviv
²Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv
³Human Genetics Faculty of Medicine, Tel Aviv University, Tel Aviv
⁴Goldschleger Eye Research Institute, Sheba Medical Center, Tel Hashomer, Tel Aviv University, Tel Aviv

Angiogenesis is an important natural process, both in health and in disease which is controlled through “on” and “off” switches. When proangiogenic factors are produced in excess of angiogenesis inhibitors, the balance is tilted in favor of blood vessel growth. A major regulator of angiogenesis is VEGF.
Protein phosphatase magnesium dependent 1A (PPM1A) was recently reported to be involved in the regulation of inflammation through diverse signaling pathways, including p38 MAPK, TGF-b and IKKa. Using PPM1A knockout mice prepared in our laboratory and corneal alkali burn we investigated the role of PPM1A in wound healing, inflammation and angiogenesis. Shortly after injury the PPM1A KO mice displayed high levels of inflammation, developed angiogenesis and failed to repair the tissue. The lack of PPM1A led to elevated expression of the TGF-b related genes including TGF-b, collagen1 and MMP-9 and finally to deregulated VEGF release and uncontrolled formation of new blood vessels.
Studying the role of PPM1A in TGF-b signaling using primary corneal fibroblasts we have found that the absence of PPM1A led to TGF-b upregulation and increased expression of angiogenic factors including TGF-b and VEGF. p38, which is phosphorylated by TGF-b in a Smad independent mode, was shown to be the immediate PPM1A dephosphorylation substrate both in cell culture and in vitro. The enhanced angiogenesis in the absence of PPM1A is a general phenomenon occuring ex vivo, in aortic ring assay and in vivo, in matrigel explants.
We propose that by direct dephosphorylation of p38, the noncanonical TGF-b substrate, PPM1A acts as the TGF-b switch and down regulates its activity during inflammation and angiogenesis. Our novel findings place PPM1A as a potential target in cancer and angiogenesis therapy.