Cellular Signaling Pathways Affected by Gene Mutations Due to Greater Paternal Agea,b
a Abbreviations: AKT, a serine/threonine-specific protein kinase, also known as protein kinase B (PKB); AR, adrenergic receptor; BRAF, a member of the RAF (rapidly accelerated fibrosarcoma) kinase family; CBL, protein encoded by Cbl gene (named after Casitas B-lineage lymphoma); CFC, cardiofaciocutaneous syndrome; CRAF, a member of the RAF (rapidly accelerated fibrosarcoma) kinase family; 4E-BP1, 4E binding protein 1; ERK, extracellular-signal-regulated kinase; FGFR, fibroblast growth factor receptor gene; GDP, guanosine 5′-diphosphate; GEF, guanine nucleotide exchange factor; GluR, glutamate receptor; GluT, glutamate transporter; GTP, guanosine 5′-triphosphate; HRAS, enzyme encoded by the Harvey RAS-1 gene; KRAS, protein encoded by the Kirsten RAS oncogene; MAPK, mitogen-activated protein kinase; MEK, a protein kinase (“mitogen-activated protein kinase/extracellular-signal-regulated kinase”); MEN, multiple endocrine neoplasia; MR, mineralocorticoid receptor; mTOR, mammalian target of rapamycin (a serine/threonine protein kinase); NMDAR, N-methyl-d-aspartate receptor; NRAS, enzyme encoded by the NRAS gene, which is associated with neuroblastoma; pAKT, phosphorylated form of AKT; PDK, phosphoinositide-dependent kinase; pERK, phosphorylated form of ERK; PI3K, phosphatidylinositide 3-kinase; PIP, prolactin-inducible protein; PKB, protein kinase B; PTEN, protein encoded by the phosphatase and tensin homolog gene; RAS, a family of proteins involved in intracellular signal transmission (from “rat sarcoma”); RET, “rearranged during transfection” gene; RHEB, RAS homolog enriched in brain; RSK2, ribosomal S6 kinase; RTK, receptor tyrosine kinase; S6K, S6 kinase; SHOC, protein encoded by “suppressor of clear homolog in C. elegans” gene; SHP2, cytosolic SH2 domain containing protein tyrosine phosphatase; SOS, protein encoded by “son of sevenless” gene; TD, thanatophoric dysplasia; TRKB, tyrosine-related kinase B; TSC, tuberous sclerosis complex. LEOPARD is a mnemonic of characteristic features.
b See references 5 and 32 for more details on these pathways. Germline disorders associated with mutations in specific genes along these pathways are indicated in boxes. The gene products that belong to the class affected by paternal age (as defined in text) are in blue, and yellow boxes indicate related disorders. Congenital disorders associated with the RAS family are known as “RASopathies.” They include the Noonan, Costello, LEOPARD, and CFC syndromes and are caused by mutations in the RTK/RAS and MAPK pathways. Other proteins in the pathway and associated germline disorders for which evidence of direct involvement in the process of selfish spermatogonial selection and paternal age effect is still lacking are indicated in black. Known tumor-suppressor genes in cancer are indicated by blue ovals. The RAS pathway is involved in many cellular processes, and some of the consequences of pathway activation are illustrated in the case of transduction occurring in a mitotically active cell (bottom, middle) or during neurotransmission and/or synaptic plasticity (bottom, left and right). Translocation of phosphorylated forms of ERK (pERK) or AKT (pAKT) into the nucleus of a mitotic cell triggers many different cellular responses, such as cell growth, proliferation, differentiation, motility, and apoptosis. Within excitatory neurons, a few examples of cellular responses triggered by the RAS or RHEB pathway are illustrated and involve molecules such as ribosomal S6 kinase (S6K and RSK2) and eukaryotic translation initiation factor 4E-BP1.