A number of tumor models have identified several key cellular signaling pathways that work independently, in parallel, and/or through interconnections to promote cancer development. Three major signaling pathways that have been identified as playing important roles in cancer include the phosphatidyl inositol-3-kinase (PI3K)/AKT, protein kinase C (PKC) family, and mitogen-activated protein kinase (MAPK)/Ras signaling cascades.[↓]
ATM : ATR : DNA-PK : FRAP1 : kinases : MAPK : mTOR : Paks : PI-3-K : PIKK : PKC : Ras : receptor tyrosine kinases : serine/threonine kinases :
The mTOR protein kinase receives stimulatory signals from nutrients as well as Ras and phosphatidylinositol-3-OH kinase (PI(3)K) downstream from growth factors. Functioning as a critical growth-control node, mTOR is the 'mammalian target of rapamycin', a fungal derivative that halts protein synthesis by complexing with immunophilin FK-506 binding protein FKBP12 peptide prolyl cis/trans isomerase.
Officially termed FRAP1 for FK506 binding protein 12-rapamycin associated protein 1, mTOR is a serine/threonine kinase that regulates regulates translation and cell division. FRAP1 (mTOR) is an evolutionarily conserved member of the phosphoinositol kinase-related kinase (PIKK) family that includes DNA-PK, ATM, ATR and several other proteins. mTOR participates in the regulation of cell growth through initiation of gene translation in response to nutrients by integratating input from multiple upstream pathways, including growth factors, mitogens, leucine, insulin, and nutrients. mTOR initiates translation by activating the ribosomal p70S6k protein kinase (S6K1) and by inhibiting the eIF4E inhibitor 4E-BP1. FRAP1 is considered to be involved in numerous additional cellular functions including actin organization, membrane trafficking, secretion, protein degradation, protein kinase C signaling, ribosome biogenesis and tRNA synthesis. mTOR may contribute to the regulation of two pathways, referred to as TORC1 and TORC2 (for TOR Complex 1 and 2).
Components of the Ras and PI(3)K signalling pathways are mutated in most human cancers. The high frequency of mutations in these pathways suggests that the loss of growth-control checkpoints and the promotion of cell survival in nutrient-limited conditions may be an obligate event in carcinogenesis.[r]
p21-activated kinases (Paks) are serine/threonine kinases that function as downstream nodes oncogenic signalling pathways. Paks are well-known regulators of cytoskeletal remodelling and cell motility that promote cell proliferation, regulate apoptosis and accelerate mitosic abnormalities, resulting in tumorigenesis and cell invasiveness. Alterations in Pak expression have been detected in human tumours
Signal transduction in cancer cells is a sophisticated process that involves receptor tyrosine kinases (RTKs) that eventually trigger multiple cytoplasmic kinases, which are often serine/threonine kinases. A number of tumor models have identified several key cellular signaling pathways that work independently, in parallel, and/or through interconnections to promote cancer development. Three major signaling pathways that have been identified as playing important roles in cancer include the phosphatidyl inositol-3-kinase (PI3K)/AKT, protein kinase C (PKC) family, and mitogen-activated protein kinase (MAPK)/Ras signaling cascades. Faivre S, Djelloul S, Raymond E. New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors. Semin Oncol. 2006 Aug;33(4):407-20.
~ activator ~ cadherins ¤ Cancer ¤ carcinogenesis ~ cyclin-dependent kinases ~ cytokines ~ gene regulation ¤ genetic predispositon~ growth factors ¤ oncogenes ¤ malignant transformation ¤ mitogens ¤ mutagens ¤ neoplasia ¤ non-mutagenic carcinogens ¤ p53 ¤ proliferation ¤ proto-oncogenes ~ promoters ¤ Ras ¤ Rb ~ receptor tyrosine kinases ~ regulatory proteins ~ replication ~ repressor ~ response elements ~ retrotransposons ~ restriction enzmes ~ reverse transcriptase ~ Rho GTPase ~ ribosomes ~ serine/threonine kinases ¤ signaling molecules ~ silencers ¤ T-antigens ¤ TP53 ~ transcription ~ transcription factors ~ translation ¤ tumor antigens ¤ tumor suppressors ¤ tumorigenic viruses ¤ viral carcinogens ¤
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