Figure 1.

Schematic diagram of cancer cells ingesting extracellular small particles, such as protein, necrotic debris, and ATP, through macropinocytosis. The activation of Ras and PI3K pathways, by oncogenic mutations, integrin αvβ3, EGFR or PDGFR, activates upstream effectors (e.g., Ras and PI3K) which then activate downstream effectors, such as Rac1, Cdc42, and Pak1, that are significant regulators of macropinocytosis. PTEN loss can activate PI3K, which is closely linked to membrane phospholipid conversion. AMPK activation can activate Rac1, which can trigger macropinocytosis, and prompt the transport of transcription factors into the nucleus, resulting in elevated expression of lysosomal genes in the nucleus. The activation of Rac1 and Cdc42 and the lysosomal degradation of macropinocytic cargos are sensitive to pH changes, which are regulated by the Na⁺/H⁺ exchanger (NHE) and the vacuolar H⁺-ATPase (v-ATPase). In the lysosome, extracellular proteins, or necrotic debris, can be degraded into amino acids, which can fuel the TCA cycle, leading to increased cell growth and survival. The lysosomal degradation process of the macropinocytosed protein into amino acids can be inhibited by mTORC1. Interestingly, AMPK can antagonize the mTORC1 pathway and improve the degradation efficiency of internalized proteins in the lysosome.