Klotho, also called Klotho-alpha, is the founding member of the Klotho family within the glycosidase-1 superfamily . Klotho is expressed in areas concerned with calcium regulation, predominantly in the kidney distal convoluted tubules, but also in the brain choroid plexus (which produces cerebrospinal fluid) and the parathyroid. A 130 kDa form found in plasma and cerebrospinal fluid is produced by proteolytic cleavage of the glycosylated 135 kDa full-length Klotho . A truncated 549 aa isoform predicted by alternative mRNA splicing has been detected in human and mice. A prominent intracellular 120 kDa form of Klotho is localized to endoplasmic reticulum and Golgi membranes. The phenotype of Klotho-deficient mice resembles premature aging, including arteriosclerosis, osteoporosis, skin atrophy, infertility, emphysema and premature death. Conversely, excess Klotho extends lifespan. Klotho acts as a cofactor for interaction of FGF-23 with FGF R1. This interaction negatively regulates 1 alpha-hydroxylase, the rate-limiting enzyme in the synthesis of 1,25(OH)2D3 (vitamin D). Klotho deficient mice show severe hyperphosphatemia and ectopic calcification of soft tissues due to excess vitamin D. Both Klotho and Klotho beta are cofactors for FGF19 binding. Klotho also shows glucuronidase activity which activates the renal ion channel TRPV5 to reabsorb urinary calcium. Klotho has been reported to downregulate insulin or IGF-1 signaling in adipocytes, to bind and antagonize Wnt molecules, and to facilitate release of parathyroid hormone.
Killer cell lectin-like receptor subfamily B, member 1(KLRB1) is a single-pass type II membrane protein which contains 1 C-type lectin domain. KLRB1 plays an inhibitory role on natural killer (NK) cells cytotoxicity. Activation results in specific acid sphingomyelinase/SMPD1 stimulation with subsequent marked elevation of intracellular ceramide. Activation also leads to AKT1/PKB and RPS6KA1/RSK1 kinases stimulation as well as markedly enhanced T-cell proliferation induced by anti-CD3. It acts as a lectin that binds to the terminal carbohydrate Gal-alpha(1,3)Gal epitope as well as to the N-acetyllactosamine epitope. Binds also to CLEC2D/LLT1 as a ligand and inhibits NK cell-mediated cytotoxicity as well as interferon-gamma secretion in target cells.
CD94 (Cluster of Differentiation 94), also known as killer cell lectin-like receptor subfamily D member 1 (KLRD1), is expressed on the surface of natural killer cells in the innate immune system. CD94 Plays a role as a receptor for the recognition of MHC class I HLA-E molecules by NK cells and some cytotoxic T-cells. CD94 Can form disulfide-bonded heterodimer with NKG2 family members. The CD94/NKG2 complex, on the surface of natural killer cells interacts with Human Leukocyte Antigen (HLA)-E on target cells. Natural killer (NK) cells are a distinct lineage of lymphocytes that mediate cytotoxic activity and secrete cytokines upon immune stimulation. Several genes of the C-type lectin superfamily, including members of the NKG2 family, are expressed by NK cells and may be involved in the regulation of NK cell function. KLRD1 (CD94) is an antigen preferentially expressed on NK cells and is classified as a type II membrane protein because it has an external C terminus.
Karyopherin Subunit α-2 (KPNA2) belongs to the importin alpha family. KPNA2 is widely expressed in many tissues and contains an N-terminal hydrophilic region, a hydrophobic central region composed of 10 repeats, and a short hydrophilic C-terminus. KPNA2 interacts with the NLSs of DNA helicase Q1 and SV40 T antigen and may be involved in the nuclear transport of proteins. KPNA2 also may play a role in V(D)J recombination. KPNA2 functions in nuclear protein importantly as an adapter protein for nuclear receptor KPNB1.
Importin subunit beta-1(KPNB1) is a member of the importin beta family. KPNB1 contains 1 importin N-terminal domain and 19 HEAT repeats. It is involved in nucleocytoplasmic transport, a signal- and energy-dependent process, takes place through nuclear pore complexes embedded in the nuclear envelope. Its functions in nuclear protein import, either in association with an adapter protein, like an importin-alpha subunit, which binds to nuclear localization signals (NLS) in cargo substrates, or by acting as autonomous nuclear transport receptor. The import of proteins containing a classical nuclear localization signal (NLS) requires the NLS import receptor, a heterodimer of importin alpha and beta subunits. Each of these subunits is part of the karyopherin family of proteins. Importin alpha binds the NLS-containing cargo in the cytoplasm and importin beta docks the complex at the cytoplasmic side of the nuclear pore complex. It mediates autonomously the nuclear import of ribosomal proteins RPL23A, RPS7 and RPL5.
K-Ras belongs to the small GTPase superfamily, Ras family. As other members of the Ras family, K-Ras is a GTPase and is an early player in many signal transduction pathways. It is usually tethered to cell membranes because of the presence of an isoprenyl group on its C-terminus. K-Ras functions as a molecular on/off switch. Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Plays an important role in the regulation of cell proliferation. Plays a role in promoting oncogenic events by inducing transcriptional silencing of tumor suppressor genes (TSGs) in colorectal cancer (CRC) cells in a ZNF304-dependent manner. Besides essential function in normal tissue signaling, the mutation of a K-Ras gene is an essential step in the development of many cancers. Several germline K-Ras mutations have been found to be associated with Noonan syndrome[4] and cardio-facio-cutaneous syndrome. Somatic K-Ras mutations are found at high rates in Leukemias, colon cancer, pancreatic cancer and lung cancer.
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