Working model of our study. PITPs deliver newly synthesized PI from the ER to PM, and MTMR at the PM concomitantly converts PI3P to PI, which are a crucial substrate for PM PPIn like PI4P. ORP5 and ORP8, the LTPs for PtdSer, exchange ER PtdSer with PM PI4P at ER-PM MCSs, which enriches PM PtdSer contents. This in turn allows stable PM binding of KRAS, and thereby KRAS signal output. When MTMR is depleted, PM PI3P conversion to PI is blocked, providing insufficient PM PI contents for PI4P synthesis. This dissociates ORP5/8 from ER-PM MCSs, resulting in reduced PM localization of PtdSer and thereby KRAS. PITPs—PI transfer proteins; PI4KA—phosphatidylinositol 4-kinase IIIα; ORP—oxysterol-binding protein–related protein; PM—plasma membrane; ER—endoplasmic reticulum.