Probable mechanism for the role of ENKUR downregulation in cell proliferation. We hypothesize that, under normal conditions, enkurin at sufficient physiological levels is bound to PI3K via the SH3-binding domain, thus regulating its activation.²⁶ However, in the setting of MPNs, downregulation of enkurin likely contributes to free PI3K and its prolonged activation, further activating Akt and potentially other signaling mechanisms, prompting overexpression of cell differentiation cycle genes, including CDC20,⁵⁹ and cell proliferation.