The five major cell signaling pathways are illustrated and described in the text. Interactions within the same pathway are shown as black arrows and blue bars: (→, positive) (, negative) Points of pathway crosstalk and convergence are highlighted with dashed arrows in black and dashed bars in blue: (, positive interaction) (, negative interaction) Question marks (?) indicate unknown beginnings or endpoints, in the crosstalk targets. For visual clarity, wavy lines are used to indicate pathway intersection (∿). Critical defects in these pathways, attributable to both age-related diseases/degenerative disorders and to aging itself, are depicted as green, red, and yellow contours/bars/arrows in order to denote upregulation/activation. (, , ) downregulation/inactivation, (, , ) or both scenarios (, , ). Some key points on the aging of signaling networks are exemplified as follows:
(a) presenilin mutations (of Notch-associated γ-secretase complex) in neural stem cells implicated in neurodegenerative disorders, such as Alzheimer’s disease y[64].
(b) attenuated β-catenin signaling is implicated in Alzheimer’s disease [9].
(c) TGFβ/Notch balance associated with skeletal muscle repair deficiency, due to elevated levels of P-SMAD present on CDK inhibitor promoter regions [72].
(d) Altered MAPK signaling in mouse liver [81], rat aorta [82], human skeletal muscle [83], mouse bone marrow stromal cells (BMSCs)/osteoblasts [84], human T cells [85] and rat basal forebrain [86].
(e) aberrant Akt phosphorylation levels in rat aorta under uniaxial stretch [82], mouse BMSCs/osteoblasts under IGF-I treatment [84], rat enterocytes [90], and rat kidney [91].
(f) exogenous Shh administration promoted revascularization and improved wound repair in mouse myocardial ischemia [93] and mouse diabetic ulcer models [94], respectively, and also protected dopaminergic neurons in a rat model of Parkinson’s Disease (PD) [96,97]; reduced Shh levels in grey and white matter of Multiple Sclerosis patients [95].
Notably, it is likely that many of these identified signaling aberrations deleteriously affect numerous targets. Deciphering these interactions, as well as uncovering other modes of pathway integration, will play a prominent role in the future development of targeted signaling manipulation for therapeutic purposes. This schematic diagram is by no means exhaustive. Many pathway crosstalk points were omitted for visual clarity, and due to manuscript length restrictions.
Abbreviations: NICD, notch intracellular domain; Su(H), suppressor of hairless; CBF1, Candida glabrata centromere binding factor 1; RBP-J, recombination signal sequence binding protein for Jκ genes; Sno, strawberry notch; HES, hairy/enhancer of split; Ac-Sc, achaete-scute; Gro/TLE, groucho/ transducin-like enhancer of split; FZD, frizzled; Dsh, disheveled; APC, adenomatous polyposis coli; GSK, glycogen synthase kinase; β-CAT, beta-catenin; TCF/LEF, T-cell factor/lymphoid enhancer-binding protein; sFRP, secreted frizzled-related protein; RTK, receptor tyrosine kinase; FGF, fibroblast growth factor; MEK, MAPK or ERK kinase; ERK, extracellular signal-regulated kinase; JNK, c-Jun amino-terminal kinases; PNT, pointed; MKP, MAPK Phosphatase; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; PDK, 3-phosphoinositide-dependent protein kinase; PTEN,; Shh, sonic hedgehog; Ptc, patched; Smo, smoothened; Fu, Fused serine threonine kinase; SuFu, suppressor of fused protein; Cos2, costal2; PKA, protein kinase A; CK1, casein kinase 1; Gli/Ci, Glioma-associated oncogene homologue/cubitus interruptus; IHOG/BOI, interference hedgehog/brother of IHOG; TGFβ, transforming growth factor beta; BMP, bone morphogenetic protein; ACT, activin type receptor; CDK, cyclin-dependent kinase; P, phosphate group.