Overall, these data indicates that pY54-H3 critically regulates functional outcomes of both, the gain and loss of SHP2 phosphatase activity; aberrantly high pY54-H3 may cause imbalance in growth characteristics and development in the male reproductive system, while in contrast, subduing pY54-H3 it could also have implications in metabolic disorders, antitumor immunity, or cancer. Here, PTPN11 is linked to metabolic disease.