In contrast, the other two components of this signaling pathway, MEK (mitogen-activated protein kinase kinase) and ERK (mitogen-activated protein kinase) were identified as cytoplasmic protein kinases activated by mitogens in the 1990s. Later, studies on viral oncogenes had also led to the discovery of a N-terminal truncated version of RAF Ser/Thr kinase (RAF1 or CRAF). This signaling pathway was discovered in the 1970s –1980s, when Ras small GTPases were identified as first oncogenes from sarcoma viruses. The Ras/RAF/MEK/ERK (MAPK, mitogen-activated protein kinase) signaling is a central pathway that regulates cellular proliferation, differentiation, and survival. In this review, we will summarize the current proceedings of how MAPK-AMPK signalings interplay with each other in cancer biology, as well as its implications in clinic cancer treatment with MAPK inhibition and AMPK modulators, and discuss the exploitation of combinatory therapies targeting both MAPK and AMPK as a novel therapeutic intervention. Recent studies have shown that AMPK signaling can also reversibly regulate hyperactive MAPK signaling in cancer cells by phosphorylating its key components, RAF/KSR family kinases, which affects not only carcinogenesis but also the outcomes of targeted cancer therapies against the MAPK signaling.
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To drive carcinogenesis, this signaling promotes cellular overgrowth by turning on proliferative genes, and simultaneously enables cells to overcome metabolic stress by inhibiting AMPK signaling, a key singular node of cellular metabolism.
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The Ras/RAF/MEK/ERK (MAPK) signaling is one of the best-defined pathways in cancer biology, and its hyperactivation is responsible for over 40% human cancer cases.
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Cancer is characterized as a complex disease caused by coordinated alterations of multiple signaling pathways.