Contextual signaling in cancer. (October 2016)

• Record Type: Journal Article
• Authors: Smithson, Laura J.; Anastasaki, Corina; Chen, Ran; Toonen, Joseph A.; Williams, Sidney B.; Gutmann, David H.
• Is Part Of: Seminars in cell & developmental biology. Volume 58(2016)
• Page Start: 118
• Page End: 126
• Publication Date: 2016-10
• Subjects: AKT protein kinase B -- ATF4 activating transcription factor 4 -- cAMP cyclic adenosine monophosphate -- CCL5 (C-C motif) ligand 5 -- CNS central nervous system -- 4EBP1 4E (elF4E) binding protein -- ECM extracellular matrix -- ERK p44/p42 extracellular signal-related kinase -- GAP GTPase-activating protein -- GRK2 G protein-coupled receptor kinase 2 -- HGG high grade glioma -- HVR hypervariable region -- iPSCs induced pluripotent stem cells -- JNK c-Jun N-terminal kinases -- MEK mitogen-activated protein kinase kinase -- MKK4 mitogen-activated protein kinase kinase 4 -- MLK3 mixed-lineage protein kinase 3 -- mSIN1 mammalian stress-activated MAP kinase interacting protein-1 -- mTOR mechanistic target of rapamycin -- mTORC1 mTOR complex 1 -- mTORC2 mTOR complex 2 -- NF1 Neurofibromatosis type 1 -- NLGN3 neuroligin-3 -- NSCs neural stem cells -- OPG optic pathway glioma -- PDPK1/PDK1 phosphoinositide dependent protein kinase-1 -- PI3K phosphoinositide 3-kinase -- PIP2 phosphatidylinositol (4, 5)-biphosphate -- PIP3 phosphatidylinositol (3, 4, 5)-triphosphate -- PKCα, β, γ protein kinase Cα, β, γ -- PKCζ protein kinase C-zeta -- PNS peripheral nervous system -- PRAS40 proline-rich in AKT substrate of 40 kDa -- Protor protein observed with rictor -- PTEN phosphate and tensin homolog -- Rac1 ras-related C3 botulinum toxin substrate 1 -- RAF rapidly accelerated fibrosarcoma -- Raptor regulatory-associated protein of mTOR -- RAS rat sarcoma -- Rictor rapamycin-insensitive companion of mTOR -- p90-RSK ribosomal S6 kinase -- SCF stem cell factor -- S6K p70 S6 kinase -- SGK1 serum- and glucocorticoid-induced protein kinase 1 -- TSC tuberous sclerosis complex; Glioma -- RAS -- mTOR -- NF1 -- Astrocyte -- Neuron -- Nervous system; Cytology -- Periodicals; Developmental biology -- Periodicals; 571.6
• DOI: 10.1016/j.semcdb.2016.06.002
• Languages: English
• ISSNs: 1084-9521

Abstract

Graphical abstract: Highlights: Cellular responses are dictated by context-dependent signaling pathway engagement. A limited number of molecules can activate multiple downstream effectors. Specific effector pathways are activated in a cell type and tissue-specific manner. Extracellular cues and genomic/genetic factors modify signaling pathway output. Abstract: The formation and maintenance of an organism are highly dependent on the orderly control of cell growth, differentiation, death, and migration. These processes are tightly regulated by signaling cascades in which a limited number of molecules dictate these cellular events. While these signaling pathways are highly conserved across species and cell types, the functional outcomes that result from their engagement are specified by the context in which they are activated. Using the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome as an illustrative platform, we discuss how NF1/RAS signaling can create functional diversity at multiple levels (molecular, cellular, tissue, and genetic/genomic). As such, the ability of related molecules (e.g., K-RAS, H-RAS) to activate distinct effectors, as well as cell type- and tissue-specific differences in molecular composition and effector engagement, generate numerous unique functional effects. These variations, coupled with a multitude of extracellular cues and genomic/genetic changes that each modify the innate signaling properties of the cell, enable precise control of cellular physiology in both health and disease. Understanding these contextual influences is important when trying to dissect the underlying pathogenic mechanisms of cancer relevant to molecularly-targeted therapeutics.