The tau of MARK: a polarized view of the cytoskeleton

Microtubule-affinity regulating kinases (MARKs) were originally discovered by their ability to phosphorylate tau protein and related microtubule-associated proteins (MAPs), and thereby to regulate microtubule dynamics in neurons. Members of the MARK (also known as partition-defective [Par]-1 kinase) family were subsequently found to be highly conserved and to have key roles in cell processes such as determination of polarity, cell-cycle control, intracellular signal transduction, transport and cytoskeleton. This is important for neuronal differentiation, but is also prominent in neurodegenerative ‘tauopathies’ such as Alzheimer's disease. The identified functions of MARK/Par-1 are diverse and require accurate regulation. Recent discoveries including the x-ray structure of human MARKs contributed to an increased understanding of the mechanisms that control the kinase activity and, thus, the actin and microtubule cytoskeleton. Microtubule-affinity regulating kinases (MARKs) were originally discovered by their ability to phosphorylate tau protein and related microtubule-associated proteins (MAPs), and thereby to regulate microtubule dynamics in neurons. Members of the MARK (also known as partition-defective [Par]-1 kinase) family were subsequently found to be highly conserved and to have key roles in cell processes such as determination of polarity, cell-cycle control, intracellular signal transduction, transport and cytoskeleton. This is important for neuronal differentiation, but is also prominent in neurodegenerative ‘tauopathies’ such as Alzheimer's disease. The identified functions of MARK/Par-1 are diverse and require accurate regulation. Recent discoveries including the x-ray structure of human MARKs contributed to an increased understanding of the mechanisms that control the kinase activity and, thus, the actin and microtubule cytoskeleton. atypical protein kinase C forms a complex with the scaffold proteins Par-6 and Par-3 and regulates cell polarity. This Par complex was initially described in the nematode C. elegans and later in the fruit fly D. melanogaster and vertebrates. one of the components of the cytoskeleton consisting of tubulin polymers. They are involved in many cellular processes including mitosis and intracellular transport. proteins that interact with microtubules and stabilize them. a family of four serine/threonine kinases in mammals that are homologues to yeast Kin1 and Par-1 in C.elegans and D. melanogaster. the Notch pathway is a highly conserved cell-signaling system present in most multicellular organisms and is important for cell–cell communication, which involves gene-regulation mechanisms that control multiple cell-differentiation processes during embryonic and adult life. Notch is a transmembrane protein whose extracellular domain binds Notch ligands, followed by signaling into the cell. the Notch ligands are also single-pass transmembrane proteins and are members of the DSL (Delta/Serrate/LAG-2) family of proteins. In D. melanogaster, there are two ligands named Delta and Serrate. Ligand proteins binding to the extracellular domain of Notch induce proteolytic cleavage and release of the intracellular domain, which enters the cell nucleus to alter gene expression. six different proteins that are required for cytoplasmic partitioning in the early embryo of C. elegans. Par-1 and Par-4 are conserved protein kinases and homologous to the mammalian serine/threonine kinases MARK and LKB1. a technique for studying protein–protein interactions. The TAP method involves the fusion of the TAP tag to the C terminus of the protein under study. The TAP tag consists of calmodulin binding peptide (CBP) from the N terminal, followed by tobacco etch virus protease (TEV protease) cleavage site and Protein A, which binds tightly to IgG. a neuronal microtubule associated protein present in six main isoforms in the human central nervous system and additional isoforms (‘big tau’) in peripheral nerves. Tau is localized in the axons of neurons, where it maintains the integrity of the axon, together with other MAPs. tauopathies are a class of neurodegenerative diseases accompanied by pathological aggregation of tau protein in so-called neurofibrillary tangles (NFT) in the human brain. signals caused by Wnt proteins, which form a family of highly conserved secreted molecules that regulate cell-to-cell interactions during embryogenesis, but are also involved in normal physiological processes in adult animals. an amino acid motif composed of phospho-Ser with proline at the +2 position and arginine or lysine at the −3 position. a family of conserved regulatory molecules expressed in all eukaryotic cells. 14-3-3 proteins have the ability to bind a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and transmembrane receptors.