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KINASES
     A typical cell in the human body has the ability to respond to change.  At any specific instant, a cell might be required to divide, increase the rate of its metabolic reactions, induce inflammation, stimulate cells around it, synthesize new proteins, etc.  Many of the enzymes which determine these responses to a new stimulus are present in the cell prior to their activation.  Therefore, one of the major aspects of gene regulation is the regulation of proteins which already have been synthesized and are present in the cytoplasm.  Perhaps the most important mechanism in the post-translational regulation of protein activity is the addition or removal of phosphate groups on amino acids of these proteins.  Many intracellular proteins are “off” until phosphate groups are added to it, at which point they are “on”.  These phosphates are added to specific amino acids of the protein (such as serine, threonine, and tyrosine).
KINASE

     Reversible protein phosphorylation is essential in signal transduction (serving as the intermediate between external signals and intracellular responses to these signals) in both eukaryotes and prokaryotes.   Animals are multicellular and use reversible phosphorylation of specific amino acids in response to both interactions between cells and between cells and the surrounding matrix (Muller, 2001).  The enzymes which transfer phosphates to these amino acids, usually from ATP, are called protein kinases.  Protein kinases compose 1-3% of the genes in eukaryotic genomes and are one of the largest families of enzymes.  There are two major groups of protein kinases which differ in the amino acid to which phosphate groups are added: protein tyrosine kinases (which can be further divided into receptor and nonreceptor PTKs) and serine/threonine kinases.  Protein tyrosine kinases are major signaling factors in metazoan animals and abnormal expression of these enzymes cause a number of human diseases.  The catalytic domain is shared in this gene superfamily although many additional domains are present in subsets of the superfamily.  The various subfamilies were expanded early in the evolution of vertebrates (Gu, 2003). 

    Bacteria also regulate proteins in signal transduction pathways through the addition and removal of phosphates from the proteins.  The main amino acids to which phosphate groups are added are histidine and aspartic acid in bacteria in contrast to the serine, tyrosine, and threonine residues used in eukaryotes.  Although the primary kinase enzymes in bacteria are different from those in eukaryotes, the eukaryotic-type of kinases do exist in some prokaryotes and there existence seems to have preceded the evolution of the eukaryotes (Ogawara, 1999; Gallinier, 1998).    Kinases may have evolved from ABC cassette transporter proteins (Plowman, 1999).  Most bacterial genomes seem to possess between one and ten serine/threonine kinase genes, which were formerly though to be unique to eukaryotes (Han, 2001).  “Eukaryotic” protein kinases in microbes include Pkn1, YpkA, Etk, Stk,Spk, and Mbk (Kenelly, 2002).  Most gram positive bacteria control their catabolic genes (which comprise about 10% of their genome) with the phosphorylation of serine residues as a catabolite corepressor using HPr kinase/phosphorylase (Mijakovic, 2002).  Anabaena possesses 66 genes for serine/threonine kinases and phosphatases, composing more than 4% of the coding genome (Wang, 2002).  The enzymes which function as arginine kinases have evolved independently at least four separate times (Iwanami, 2009). Eubacteria are pictured below.

BACTERIA

     Plant receptor-like kinases (RLKs) possess a signal sequence, a transmembrane region, and a cytoplasmic kinase domain and function in diverse signaling pathways which include meristem development, leaf development, bacterial resistance, and self-incompatibility.  As of 2001, there are more than 9000 different RLKs and related kinases identified in plants.  RLKs form a gene family of serine/threonine/kinases which include the Pelle kinases in animals as part of their clade.  Drosophila and C. elegans possess one gene in the RLK family while humans possess three.  This gene family has undergone a great deal of amplification in higher plants: while liverworts possess one family member and pines about twenty, Arabidopsis has over 300 and Glycine max over 700 family members.  In Arabidopsis, more than 1/3 of the RLKs are in tandem repeats of 2-19 genes and RLK subfamily members are often located together on a chromosome (Shiu, 2001).  Phytochromes are serine/threonine kinases that detect light (such as red and far red wavelengths) and subsequently initiate responses to light. Some bacteria possess a histidine kinase homologous to plant RLKs (Yeh, 1998).  Kinases are involved in signaling between plants, fungi, and their bacterial endosymbionts (Kister, 2002).

     Yeast possess more than 130 protein kinase genes in their genome (about 2% of their genome) while humans possess more than 1000 (about 1-3% of the genome) (Tomaska, 2000).  Yeast kinases include members of the MAPK, MAP2K, MAP3K casein kinase I and II families and others including CDC activated protein kinase and histidine kinases (homologs of the main group of kinases known from eubacteria).  While there are no receptor tyrosine kinases known in yeast, there are a few kinases which can phosphorylate serine, threonine, and tyrosine (Hunter, 1997).  Of 120 kinase enzymes known in yeast, only 23 belong to yeast-specific gene subfamiles.  The others are members of subfamilies found in higher organisms (Manning, 2002). 

     Although there are many protein kinase genes in the nuclear genomes of eukaryotes, there are relatively few mitochondrial protein kinases, indicating that mitochondrial function is less dependent on signaling pathways occurring inside the mitochondria (Tomaska, 2000).

 

PLANARIAN

     There is evidence that the receptor tyrosine kinases, once thought to be specific to animals, evolved in the unicellular ancestors of animals.  While receptor tyrosine kinases are known primarily in metazoan animals (such as the planarian pictured above) where they are involved in many essential signaling pathways involved in animal development, a receptor tyrosine kinase is known from the protistan group choanoflagellates.  A number of genetic studies have indicated that choanoflagellates are the closest protistan relatives of the metazoans, which is supported by their possession of important animal genes not known from any other eukaryotic group (King, 2001).

     As will discussed in other chapters, it appears that majority of the genome of higher animals resulted from duplications of ancestral genes in smaller ancestral genomes.  Ancestral genomes seem to have created much of their diversity by “domain shuffling”—exchanging small functional protein domains from separate proteins and combining them in new ways.  The majority (if not all) of the domain shufflings which produced the various subfamilies of the protein tyrosine kinase gene family had occurred before the split of sponges and higher animals.  The same observation is true of other gene families such as protein tyrosine phosphatase and phosphodiesterase families (Suga, 2001; Suga, 2008).  Sponges possess a receptor protein kinase which possesses an immunoglobulin domain, receptor tyrosine kinases, and non-receptor PTKs  members of the Src and Fes families (Schacke, 1994b; Gamulin, 1997; Steele, 1999).  The tyrosine kinases in sponges appear to be distantly related to the genes for insulin and insulin receptors. (Muller, 1999).  While nematodes and fruit flies possess two src kinase genes each, the sponge Suberites domuncula possesses five genes in its genome (Cetkovic, 2004).  Sponge cells are depicted below.

SPONGE

In cnidarians such as Hydra, there are three related protein tyrosine kinases in which one of them has apparently been modified for a unique function since it only possesses a substrate-binding domain (and lacks the ATP binding domain) (Kroiher, 2000). 

     Of just under 20,000 genes in C. elegans, about 500 kinases, 185 phosphatases, and 128 phosphoprotein-binding domains are known.  Protein kinases represent the second most abundant protein domain in the worm genome (after seven transmembrane chemoreceptors and ahead of zinc finger transcription factors).  There are a number of kinase signaling cascades which exist in both worms and humans such as the AGC group of kinases (homologous to AKT and PDK1 in mammals), CAMK group (including death associated protein kinases, MAPK-associated kinases, myosin light chain kinase, and phosphorylase kinase), CMGC group (including the cyclin depenednet kinases, GSK-3, MAPKs, and CLK), STE group (including homologs of mammalian RAF, MLK, and TAK1 genes), receptor tyrosine kinases (the largest group of kinsaes in all higher eukaryotes from worms to humans), and the protein-tyrosine kinase group.  The CAMK group of kinases is absent from yeast and help multicellular organisms reach greater complexity.  The RCK gene family (which includes seven genes in humans in addition to genes in worms) is also absent in yeast.  Worms and humans both have more than twice the number of MAP kinases known in yeast (Plowman, 1999).

     There are about 94 subfamilies of kinase enzymes which are only known from animals.  A number of kinase subfamilies are only known in coelomate animals (and not in C. elegans) such as Jak A, JakB, Syk, Tek, Slob, Ste20 NinaC, CCK4, Musk, Ret, PDGF/VEGFR, Sev, Lisk, Mos, TOPK, Trb, and CDK10 (Manning, 2002).  A number of these are expressed in the nervous system which has achieved a greater complexity in coelomates.  Four of these subfamilies help to regulate the cell cycle (Manning, 2002).  Several kinase families which function in the human immune system, nervous system, development, and the control of cell division are also present in protostome coelomates such as flies (Manning, 2002).   G-protein coupled receptors, one of the largest families of genes in mammals, can be regulated by protein kinases.  This is true in invertebrates as well and Drosophila possesses genes which are homologous to those which regulate rhodopsin and b adrenergic receptors in mammals (Cassill, 1991).

     The pufferfish possesses a protein tyrosine kinase whose control elements can substitute for the equivalent region in the homologous mammalian gene involved in T cell function.  This demonstrates that the sequences for lymphocyte-specific expression of this gene are conserved in higher gnathostomes (Brenner, 2002).  

 

MITOGEN ACTIVATED KINASES

mapk

     The diverse phyla of living things have very similar intracellular concentrations of sodium, potassium, and other electrolytes.  MAP kinase cascades are important pathways which regulate the cell cycle in response to osmotic stress (Kultz, 1998).   The MAPK family has 3 subgroups: the extracellular signal kinases (ERKs), the stress-activated protein kinases (SAPKs) and the MAP3K subgroup.  ERK subgroup members are known in plants, yeast, and animals; the SAPK subgroup members are known from animals and yeast; and the MAP3K subgroup is known from animals and protozoans (Kultz, 1998). Higher animals use the p38 pathway in responses to stress and microbes, using SAPK2 (stress activated protein kinase), a member of the MAPK gene family.  Sponges possess a homolog of this important group in higher animals (Bohm, 2000).

     MAP kinase pathways very important in the control of cell division and differentiation.  They can phosphorylate diverse targets ranging from transcription factors to cytoskeletal proteins.  MAP kinase pathways are important in plant growth and development and plant genomes include MAPK, MAP2K, MAP3K, and MAP4K genes, as do animal genomes (Jouannic, 1999).  Yeast genomes include 5 different MAP kinase signaling pathways (Jouannic, 1999).  In yeast, Ste20 related kinases function of upstream in MAP3K signaling pathways.  Worms, flies, and humans use this pathway in development (Su, 1998). The incorporation of MAP kinase cascades in innate immunity is an ancient animal mechanism, known from both nematodes and higher animals (Kim, 2002). 

      In mammalian cells, ras activates the MAP kinase cascade through the serine/threonine kinase Raf.  In yeast, Ras also activates a MAP kinase cascade (Gilbreth, 1996).  Yeast and other fungi utilize the MAP kinase cascade for a variety of functions including mating and pathogenicity (Lev, 1999).  In plants, the MAP kinase cascade also functions in the defense from toxins (Frye, 2001).  The following are descriptions of the functions of MAP gene family members in the human genome.

 

MAP4K1 is involved in hematopoeisis and is expressed in the bone marrow and fetal liver (Jouannic, 1999).

 

MAP4K3 is ubiquitously expressed.

 

MAP4K4 is expressed as two different isoforms, one of which is present in the brain only.

 

Mos is a MAP3K kinase which functions in vertebrate and invertebrate oocytes to regulate the second meiotic division and to prevent mitosis until after fertilization (Tachibana, 2000).

 

MAP3K1 can protect cells from apoptosis.

 

MAP3K3 is required for angiogenesis.

 

MAP3K4

 

MAP3K5

 

MAP3K6 is most highly expressed in the heart and skeletal muscle.  Cardiac muscle is depicted in the following image.

CARDIAC

MAP3K7

 

MAP3K8 is a proto-oncogene.

 

MAP3K10 is most highly expressed in skeletal muscle.

 

MAP3K11

 

MAP3K12 contains two regions which are putative leucine zippers.  It forms homodimers and can autophosphorylate itself.

 

MAP3K13 has a leucine zipper and is expressed in the brain, liver, and placenta.

 

MAP3K14 is part of the signal cascade of lymphotoxin B receptors.

 

MAP kinases require dual phosphorylation on threonine and tyrosine residues; MAP2Ks accomplish this.  Higher eukaryotes have at least 4 specific MAP2Ks (Jouannic, 1999).

MAP2K1 mutations can be embryonic lethal.

 

MAP2K2

 

MAP2K3

 

MAP2K4 is induced by Ras and growth receptors.  In mice, null mutations cause death in embryonic development.  C. elegans possesses homologous enzymes which function in resistance to microbes; plants use homologues for pathogen resistance.

 

MAP2K6

 

MAPK1, when activated, moves to the nucleus where it phosphorylates targets there.  It forms homodimers as do other members of the MAPK family.

 

MAPK3 is expressed in the developing thymus and is involved in the plasticity of the developing visual cortex and other brain regions.

 

MAPK4 mutations in mice cause death in fetuses due to problems with blood vessel and heart development.  The heart of an embryonic pig is depicted below.

HEART

MAPK7

 

MAPK8 binds to c-JUN.  It is needed for UV light induced apoptosis and functions in T cell proliferation and differentiation.

 

MAPK9

 

MAPK11

 

MAPK12

 

MAPK14 plays a role in the delay of the G2 phase of the cell cycle after UV light damage and in erythropoeisis.

 

MAPKAPK2

 

MAPKAPK3 activates CREB genes.

 

MAPKAPK5 increases after inflammation.

 

     A mammalian serine/threonine kinase known as the nemo-like kinase (Nlk) shares homology with both MAP kinases and cyclin dependent kinases.  Homologs have been conserved in bilaterans (Kortenjann, Monika).

 

TYROSINE KINASES

ABL1 is a cytoplasmic and nuclear kinase involved in differentiation, division, adhesion, and stress responses.  It is widely expressed with higher expression in bone and cartilage.  Mutations can cause leukemia (blood from a leukemia patient is pictured below).

LEUKEMIA

APOPTOSIS-ASSOCIATED TYROSINE KINASE; ATK can cause apoptosis in the bone marrow.

 

AXL is a proto-oncogene whose mutations can cause leukemia.

 

B LYMPHOCYTE SPECIFIC TYROSINE KINASE; BLK

 

BONE MARROW KINASE; BMX seems to have a redundant role in angiogenesis.  Mutant mice have no observable abnormalities.

 

BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE; BTK is necessary in the development of B cells.  Mutations increase the risk of bacterial infections and may cause the absence of circulating B cells.

 

CDC-LIKE KINASE 1-CLK1 phosphorylates serine/arginine rich proteins needed to splice pre-mRNAs.

 

CDC2 INHIBITORY KINASE

 

CYTOPLASMIC TYROSINE KINASE; CSK is expressed in all tissues where it downregulates Src and can limit its oncogenic potential.

 

DISCOIDIN DOMAIN RECEPTORS

DDR1 is expressed in epithelia

 

DDR2

 

DUAL SPECIFICITY TYROSINE PHOSPHORYLATION-REGULATING KINASES

DYRK1A is expressed in the frontal lobe and affects neural function in mice.  It is a candidate for causing some of the mental deficits in Downs syndrome.

 

DYRK1B mutations are involved in some cancers.

 

DYRK2 and DYRK3 are highly expressed in the testis after the onset of spermatogenesis.  Human sperm are depicted below.

SPERM

EPHRIN RECEPTORS

     There are a number of ephrins and subsequently there is a variety of receptors for them.  The receptors include a kinase domain, an extracellular region, and 2 fibronectin repeats which are cysteine-rich.

EPHA1

 

EPHA2 is expressed in epithelia.

 

EPHA3 is most highly expressed in the placenta and may have a role in some tumors of the lymphatic system.

 

EPHA4 mutations in mice cause an absence of a corticospinal tract and anterior commissure.

 

EPHA5 is primarily expressed in the nervous system.  Below is a photo of spinal cord glia and axons.

AXONS

EPHA6 is expressed in distinct populations of neurons.

 

EPHA8 mutations affect the pathways of axons in the tectum.

 

EPHB1 is expressed in the floor plate of the hindbrain and functions in learning.

 

EPHB2 modifies the strength of synapses and functions in the pathfinding of developing axons.

 

EPHB3 is expressed in embryonic cells and in the epithelia of proliferating colorectal cancer.

 

EPHB4 is expressed in the fetal brain (but not in the adult brain) and functions in myeloid hematopoeisis.  It has a role in angiogenesis and capillary remodelling; these processes may make its expression a factor in the development of some cancers.  The brain of a fetal chick is depicted below.

BRAIN

EPHB6 suppresses the development of neuroblastoma.

 

ERBB2 can be involved in several human cancers including breast and prostate cancer.  Increased expression causes resistance to taxol and thus chemoresistance in cancer patients.  One polymorphism (Val655to ile) increases the risk of breast cancer.  African populations have a lower frequency of this allele and thus a lower risk of breast cancer.  (Cells of a breast cancer are pictured below.)

CANCER

ERBB3 expression is increased in some cancers.

 

ERBB4 functions in cell proliferation, differentiation, and synapse formation.  A neuromuscular junction is depicted in the following image.

NEUROMUSCULAR

The human genome possesses four proteins known as neuregulins which bind to ErbB receptor tyrosine kinases. Structurally, they possess an EGF-like domain and, depending on how the 20 exons are spliced, may possess an immunoglobulin domain as well. The expression patterns of two of the immunoglobulin-containing isoforms (Types I and IV) of Neuregulin 1 seem to play a role in susceptibility to schizophrenia. The EGF domain interacts with the ErbB3 and ErbB4 receptors, which then interact with ErbB2 ( Harrison, 2006).

 

FIBROBLAST GROWTH FACTOR RECEPTORS

FGFR1 mutations cause skeletal disorders, cancer, Pfeiffer syndrome and Kallman syndrome (which may include cleft palate, multiple dental agenisis, an absence of the corpus callosam, fusion of the fourth and fifth metacarpals, and hearing loss).

 

FGFR2 mutations cause Crouzon Syndrome, Jackson-Weiss Syndrome, Pfeiffer Syndrome, Apert Syndrome, Beare-Stevenson Syndrome, Cutis Gyrata Syndrome, and craniosyntosis (OMIM).  Mutations in FGF receptor proteins 2 aqnd 3 can cause syndactyly of hands and feet; brachdactyly, finger-like thumbs, triphalangeal thumbs, fusion of ankle and wrist, and tibial curvature, among other changes (Manouvrier-Hanu, 1999).

 

FGFR3 mutations can result in many of the syndromes also caused by mutations in FGF2.  These mutations affect cartilage development and endochondral bone and epiphyseal plates.  Mutations can also cause hyperpigmentation and some cancers.

 

FGFR4 mutations play a role in some breast and lung cancers.

 

FPS/FES-RELATED TYROSINE KINASE; FER is expressed in lymphocytes and functions in the response to integrin.

 

FMS-RELATED TYROSINE KINASE

FLT1 is involved in angiogenesis.

 

FLT3 is involved in hematopoeisis and mutations can cause leukemia.

 

FLT4 binds VEGFC and is involved in angiogenesis.  Mutations can cause lymphedema.

 

FYN ONCOGENE is related to Src and is involved in the signaling pathway of the cellular prion protein.

 

FYN-RELATED KINASE; FRK is most highly expressed in epithelia and in breast and lung cancers.  The epithelia of the intestine is depicted below.

EPITHELIA

GROWTH ARREST SPECIFIC GAS6 may have a role in coagulation.

 

HEMATOPOEITIC CELL KINASE is involved in the hematopoeisis of leukocytes.

 

INSULIN RECEPTOR is similar to the proto-oncogenes ABL and MET.

 

JANUS KINASE 3; JAK3 is involved in cytokine receptor signaling in lymphocyte development and is expressed in natural killer cells.  Mutations cause a form a SCID almost identical to the more common X-linked form.

 

KITA mutations cause piebaldism, mast cell leukemia, G1 stromal tumor, and germ cell tumors.

 

The enzyme superoxide dismutase protects against reactive oxygen species. Eukaryotes share a regulatory pathway which inhibits this enzyme using LAMMER kinases (also known as CDC2-like kinases). This family of serine/threonine kinases is shared among eukaryotes and shares function in organisms as diverse as fruit flies and humans (James, 2009).

LEUKOCYTE TYROSINE KINASE; LTK may function in signal transduction during hematopoeisis.

 

LYMPHOCYTE SPECIFIC PROTEIN TYROSINE KINASE; LCK functions in T cell development.

 

MEGAKARYOCYTE-ASSOCIATED TYROSINE KINASE; MATK functions in the differentiation and growth of megakaryocytes.  It is also expressed in the brain and may be involved in some breast cancers.

 

MER TYROSINE KINASE PROTO-ONCOGENE; MERTK is expressed in blood cells, the bone marrow and the epithelia of reproductive organs.  Mutations cause retinitis pigmentosa.

 

MET mutations can cause renal cell carcinoma and childhood hepatocellular carcinoma.

 

MACROPHAGE STIMULATING FACTOR 1 RECEPTOR; MSTR1 activates macrophages and functions in their proliferation and migration.

 

Oocytes utilize the MAP kinase pathway to regulate the cell division arrest that occurs during oogenesis. In all metazoan animals, this is regulated by a kinase known as Mos (Amiel, 2009).

MUSCLE, SKELETAL, RECEPTOR TYROSINE KINASE; MUSK is expressed in skeletal muscle.  Mutant mice lack neuromuscular junctions.

 

NSK2 RECEPTOR TYROSINE KINASE 2 functions in hematopoeisis and is expressed in most tissues.

 

NEUROTROPHIN RECEPTORS

    Neurotropins are expressed in both the CNS and PNS.

The three neurotrophin receptors (the Trk family of tyrosine kinase receptors) play an important role in the development of complexity in vertebrate nervous systems. Trk receptors are also known in lancelets and mollusks as well and the lancelet receptor can bind to mammalian neurotrophins. Trk receptors arose through the fusion of multiple ancestral domains which are found in the simplest animals such as cysteine-rich regions, immunoglobulin-like domains, leucine rich regions, and the tyrosine kinase domain. Most of these domains had joined before the common ancestor of coelomates and by the evolution of cephalochordates immunoglobulin domains had been added producing all of the domains of vertebrate receptors joined into a single protein (Benito-Gutierrez, 2006).

NTRK1 is involved in the signal transduction of NGF.  Mutations can result in an insensitivity to pain.

 

NTRK2 is involved in the response to BDNF and NTF3 and is important in the functioning of cerebellar neurons (pictured below).

NEURON

NTRK3 mutations cause medullablastoma, a tumor which affects children.

 

PROTEIN TYROSINE KINASE 2; PTK2 is ubiquitously expressed with its highest expression in the brain.  Its function links the Src and Crk oncoproteins.

 

PROTEIN TYROSINE KINASE 2B; PTK2B is a substrate for the Src family of kinases.  It functions in the cytoplasm, where it binds receptors for growth factors.

 

PROTEIN TYROSINE KINASE 6; PTK6 is expressed in breast cancer tissue but not in normal breast tissue.

 

PROTEIN TYROSINE KINASE 7; PTK7

 

PROTEIN TYROSINE KINASE 9L; PTK 9L is expressed in a variety of tissues.

 

RET ONCOGENE RECEPTOR KINASE mutations can causeendocrine neoplasia, Hirschsprung disease, and medullary thyroid carcinoma.

 

RECEPTOR TYROSINE KINASE-LIKE ORPHAN RECEPTORS

ROR1 is expressed in the heart, lung, and kidney.  Mutations in mice cause death due to respiratory problems.

 

ROR2 is expressed in chondrocytes and mutation sin humans cause brachydactyly and Robinow syndrome.  Mutations in mice cause abnormalities in endochondral bone.  Human cartilage is depicted below.

CARTILAGE

RRKAR1A has tissue specific isoforms which function in a variety of processes including transcription, learning, and metabolism.  Mutations cause Carney Complex and Adrenocorticla Disease.

 

RYK RECEPTOR-LIKE TYROSINE KINASE mutations in mice cause the formation of crania which are smaller and more rounded in addition to a shorter snout and limbs.

 

PROTEIN KINASE SYK; SYK is also known as spleen tyrosine kinase.  Mutations cause abnormalities of lymphatic vessels and hemorrhage in embryos.  Mammals have two Syk genes (Syk and  ZAP-70) whose major known function is signal transduction in immune reactions.  Syk is present in cnidarians where it interacts with surface receptors (Steele, 1999).

 

T CELL TYROSINE KINASE EMT functions in the response to integrin.

 

TEC PROTEIN TYROSINE KINASE functions in hematopoeisis.

 

ENDOTHELIAL TEK TYROSINE KINASE; TEK is expressed on endothelial cells where it binds angiopoeitin 1.  Mutations cause malformations of veins and may be lethal in mice.

 

TYROSINE KINASE WITH Ig AND EGF FACTOR HOMOLOGOUS DOMAINS; TIE

     TIE is expressed in endothelia and is needed for the development of the right side of the venous system but not the left.  It is involved in angiogenesis and mutations can cause the formation of blood vessels which leak.

 

PROTEIN TYROSINE KINASE TYK

TYK1 mutations in mice cause an abnormal ration of CD4 to CD8 cells.

 

TYK2 is expressed in lymphatic tissues, such as in the lymph node pictured below.

IMMUNE

TYRO3 PROTEIN KINASE is involved in autoimmunity and mutations in mice cause the proliferation of lymphocytes.

 

WEE1 TYROSINE KINASE is a nuclear protein which insures that DNA replication is completed before mitosis begins.  It is homologous to the wee cell cycle mutant in yeast.

 

ZETA CHAIN-ASSOCIATED PROTEIN KINASE; ZAP70 is expressed on T cells and natural killer cells.  Mutations can result in T cell immunodeficiencies.


 

 

SERINE/THREONINE KINASES

STK2 is expressed in the heart and other tissues.

 

STK3 phosphorylates myelin basic protein.  A myelin axon sheath is depicted below.

AXON

STK4 can phosphorylate itself and myelin basic protein.  It is cleaved by caspase 3 and may phosphorylate histone H2B for chromosome condensation at apoptosis.

 

STK6 is upregualted in G2/M part of the cell cycle and decreases after mitosis.  It localizes to spindle poles and probably function sin chromosome segregation like its homolog in yeast.  A dividing whitefish cell is depicted below.

MITOSIS

STK10

 

STK11 mutations cause Peutz Jeghers syndrome with abnormal melanocyates in the lips, mouth , and digits and an increased risk of tumors.  Mutations have been observed in testicular tumors, pancreatic cancer, and melanoma.

 

STK12 suppresses cytokinesis and is associated with multinuclearity and polyploidy.

 

STK13 is homologus to Drosophila and yeast proteins which are involved in centromere and chromosome separation.

 

STK15 is associated with centrosomes and is involved in their duplication.  Mutations can cause centrosome abnormalities, aneuploidy, and some cancers.

 

STK16 overexpression causes the Golgi to break up into vesicles; it may be involved in the formation of vesicles from the Golgi and secretion.

 

STK17A and STK17b induce apoptosis.

 

STK18 is expressed in the testis and thymus.

 

STK19 is expressed ubiquitously and localizes to the nucleus.

 

STK21 is expressed in keratinocytes, the brain, spleen, lungs and testis.  Mutant mice die of seizures and display high levels of apoptosis in the hippocampus and cerebellum and reduced numbers of neurons in the olfactory bulb.

 

STK22C is expressed in some stages of spermatogenesis.

 

STK24 is ubiquitously expressed.

 

STK25 is expressed throughout the body but is most highly expressed in the brain and testis.  In yeast it function upstream of MAPK cascades.

 

STK31 is expressed in the testis and possesses a domain seen in RNA-interacting proteins.

 

STK33 is most highly expressed in the testis.  It is expressed in a variety of tissues but not in the nervous system.

 

STK36 affects the transcriptional activity of GLI1 and GLI2.

 

STK38 is most highly expressed in leukocytes, such as those in the Peyers patch below.

LYMPHOCYTES

STK39 is cleaved by caspases.

 

 

 

ACTIVIN RECEPTORS

ACVR1 is a subunit in both activin and inhibin receptors.

 

ACRL1 is involved in the development of arteries and veins.  Mutations cause telangiestasia and hereditary hemorrhage.

 

ACVR1B muations cause pituitary tumors and pancreatic carcinoma.

 

 

ONCOGENE AKT1 is the target of PI3K and is involved in G1 arrest.  p27 cannot cause growth arrest when AKT1 is expressed.

 

ACTIVATOR OF S-PHASE KINASE; ASK has a role in the G1/S transition.  Most cancer cell lines have increased expression of this kinase.  CDC7C1 may phosphorylate ASK.

 

BONE MORPHOGENETIC PROTEIN RECEPTORS are related to activin receptors.

 BMPR1A is most highly expressed in skeletal muscle.  Male mammals required for the regression of Muellerian ducts.  Mutations cause juvenile polyposis syndrome.

 

BMPR1B is most highly expressed in the prostate and brain; its expression is decreased in prostate tumors.

 

CALCIUM-CALMODULIN DEPENDENT SERINE/THREONINE KINASE; CASK is involved in brain development, synapse formation, and the establishment of NMDA receptors.

 

CASEIN KINASES

Casein kinase II is involved in the response to ultraviolet light in eukaryotes from yeast to humans; it is also involved in circadian rhythms in diverse eukaryotes including plants, fungi, flies and mammals.  Not only is there a common ancestral mechanism involved in eukaryotic time-keeping, it may have evolved from mechanisms which functioned in the prevention of ultraviolet light damage (Lin, 2002).  Casein kinase II functions in cell cycle regulation in fungi and animals.  Human and worm proteins can substitute for the function of yeast proteins in yeast (Dotan, 2001).  While virtually all recognize tyrosine, serine, or threonine targets which are associated with basic and/or hydrophobic amino acids, one family (which include casein kinases and a yeast kinase) can phosphorylate acidic regions and may represent an early offshoot of the protein kinase family (Facchin, 2002). 

 

CSNK1D is ubiquitously produced in the nucleus where it is involved in DNA replication.

 

CSNK1E phosphorylates the Per gene product in Drosophila which governs biological rhythms.

 

CSNK1G1 is ubiquitously expressed.

 

CSNK1G3

 

CSNK2A2 phosphorylates p53 in response to UV light exposure and other proteins such as casein.  In Drosophila it is involved in circadian rhythms.

 

CSNK2A1 is also involved in circadian rhythms in Drosophila.

 

CSNK2B

 

CHECKPOINT KINASES

CHEK1 mutations lack the G2/M checkpoint following damage to DNA.

 

CHEK2 is activated after DNA damage.  Both  CHEK 1 and 2 may phosphorylate CDC25C to prevent mitosis.  Muations cause the Li-Fraumeni Syndrome and may be involved in some bone marrow, breast, and prostate cancers.

 

CONSERVED HELIX-LOOP-HELIX UBIQUITOUS KINASE; CHUK is a multi-domain protein with a helix-loop-helix, serine/threonine kinase and leucine zipper domains.  There are two alternate transcripts which are both ubiquitously expressed.  Mutations in mice cause abnormal skeletal development and mice die within hours of birth.

 

DEATH ASSOCIATED PROTEIN KINASE 3; DPAK3 is involved in apoptosis.

 

DOUBLECORTIN- AND CALMODULIN KINASE-LIKE 1; DCAMKL1 is most highly expressed in the brain.

 

DYSTROPHIN MYOTONICA PROTEIN KINASE mutations cause myotonic dystrophy.  Alternate transcripts are produced in muscle and in the brain.

 

ELONGATION FACTOR 2 KINASE functions in the movement of ribosomes on mRNA strands in eukaryotic translation.

 

ELKL MOTIF KINASE; EMK1 is expressed in many tissues.

 

FAS-ACTIVATED SERINE/THREONINE KINASE functions in FAS mediated apoptosis.

 

G PROTEIN COUPLED RECEPTOR KINASE 2-LIKE; GPRK2L is responsible for receptor desensitization.  It interacts with arrestin in activated receptors and prevents signal transduction.

 

B-ADRENERGIC RECEPTOR K1; ADRBK1 phosphorylates activated B adrenalin and related receptors.  It is in the same subfamily with both the preceding and following genes.

 

RHODOPSIN KINASE causes the rapid desensitization of rods, inactivating them after they have been exposed to light.  Mutations cause night blindness in Oguchi Disease.

 

GSK3A is in the Wnt pathway and may be involved in the function of presinilin and tau proteins in Alzheimers disease.

 

GSK3B is involved in metabolism and neural development.

 

HOMEODOMAIN-INTERACTING PROTEIN KINASE

HIPK2 phosphorylates p53 and CREB binding protein.

 

HIPK3 interacts with homeodomains and localizes to the nucleus.

 

INHIBITOR OF KAPPA LIGHT CHAIN GENE ENHANCER IN B CELLS, KINASE OF

IKBKB binds DNA to decrease inflammation and is involved in immunity of the skin.

 

IKBKE is part of the host anti-viral response and induces the transcription of interferon.

 

INTEGRIN-LINKED KINASE; ILK is part of the signal transduction pathway which follows the binding of integrin.

 

INOSITOL 1,3,4-TRISPHOSPHATE 5/6-KINASE; ITPK1 is most highly expressed in the brain.

 

LIMK are kinases which also possesses a LIM domain.

LIMK1 is involved in brain development.

 

LIMK2 is involved in rho-induced reorganization of the cytoskeleton.  There are two alternate transcripts with different patterns of tissue expression.

 

MAPK-INTERACTING SERINETHREONINE KINASES

MKNK1

 

MKNK2 reacts with estrogen receptors.

 

MAP/MICROTUBULE AFFINITY REULATING KINASE

MARK1 has its highest expression in the testes and brain.

 

MARK3 phosphorylates microtubles

 

MARK4 is ubiquitously expressed.

 

MALE GERM CELL-ASSOCIATED KINASE; MAK is almost exclusively expressed in the testes.

 

MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE; MELK is expressed in the gonads.

 

NEVER IN MITOSIS GENE A-RELATED KINASES

NEK2 overexpression causes centrosomes to split and lose their material resulting in microtubule disorganization.  It is expressed at its highest levels in G2 and there is almost none produced in G1.

 

NEK3 is homologoust to Aspergillus proteins involved in mitosis.  If NEK3 is absent, the cell cycle is arrested in G2.  Overespression causes premature mitosis.

 

NEK6 is ubiquitously expressed.

 

NEK7 is expressed in a variety of tissues.

 

p21/CDC42/RAC1-ACTIVATED KINASE 1; PAK1 functions in the diassembly of stress fibers and adhesions.

 

PANTOTHENATE KINASE 2; PANK2 is an essential regulator of acetyl CoA biosynthesis in yeast and flies; null mutations are lethal.  Some human mutations are linked to neurodegenerative disorders.

 

p21-ACTIVATED KINASE 2; PAK2 is ubiquitously expressed.

p21-activated kinases (PAKS) are conserved from yeast through humans and regulate mitosis (Gilbreth, 1998).

 

PCTAIRE PROTEIN KINASES are part of a subfamily related to cdc2 and cdc3 kinases in humans.

PCTK1

 

PCTK2

 

PCTK3

 

PAS-DOMAIN CONTIANING SERINE/THREONINE KINASE; PASK is conserved in eukaryotes.  It is ubiquitously expressed with a higher expression in the testis and some parts of the brain.  Cells of the human testis are depicted below.

TESTIS

POLO-LIE KINASE; PLK is homologous to Drosophila proteins which function in mitosis.  It localizes to the mitotic spindle and its expression is increased in many cancers.  PLK is depleted by p53 leading to DNA damage and apoptosis.

  All cells can utilize polyphosphate, a polymer composed of multiple (up to hundreds) of phosphate monomers joined by bonds similar to those of ATP, formed by polyphosphate kinases (Hooley, 2008).

PROTEIN KINASE, INTERFERON-INDUCIBLE DOUBLE-STRANDED RNA-DEPENDENT ACTIVATOR; PRKRA binds to double stranded RNA and is involved in interferon and growth pathways.

 

PROTEIN KINASE, cAMP-DEPENDENT, CATALYTIC is a cAMP dependent protein kinase which forms as a tetramer of 2 regulatory units and 2 catalytic units.  Humans possess 4 different regulatory proteins and 3 catalytic proteins.

PRKACA

 

PRKACB

 

PRKACG

 

PROTEIN KINASE C-LIKE 1; PRKCL1

 

PROTEIN KINASE D2 possesses zinc finger motifs and is capable of autophosphorylation.

 

PRKDC is a nuclear protein which binds broken DNA ends and functions in repair.  Mutations prevent recombination in B and T cell recepotrs.

 

PRKCA is the receptor for phorbol ester.  Mutations cause melanoma and pituitary tumors.

 

PROTEIN KINASE C, THETA FORM; PRKCQ functions in T cell maturation.

 

PRKCM binds the trans-Golgi surface and regulates the transport of vesicles to the cell surface.

 

PRKCN is ubiquitously expressed.

 

PRKCG mutations cause neurodegeneration and spinocerebellar ataxia.

 

PROTEIN KINASE, LYSINE DEFICIENT

PRKWNK1 mutations can cause pseudohypoaldosteronism.  It is expressed in the kidneys and a number of other tissues, especially those involved in chlorine and iron transport.

 

PRKWNK2 can phosphorylate myelin basic protein.

 

PRKWNK4 is expressed almost exclusively in the kidney in the DCT and collecting duct.  Mutations cause pseudohypoaldosteronism.

 

PRKY is so similar to PRKX on the X chromosome that it can result in recombination and XX males.

 

PRKX functions in the tubule formation of kidney development.  Related genes include several genes in worms and the gene family is thought to direct cellular morphogenesis in higher eukaryotes.

 

PROTEIN SERINE KINASE H1

 

RECEPTOR-INTERACTING PROTEIN KINASE

RIPK1 interacts with FAS and TNK receptors to cause apoptosis.

 

RIPK2 regulates apoptosis in the FAS receptor pathway.

 

RIPK3 is involved in caspase pathways.

 

RIBOSOMAL PROTEIN S6 KINASE, 90-KD

RPS6KA1 regulates apoptosis.

 

RPS6KA2 is most highly expressed in skeletal muscle and the lung.  It localizes to the nucleus and autophosphorylates itself.

 

RPS6KA6 is most highly expressed in the kidney and the brain.

 

RHO-ASSOCIATED COILED-COIL-CONTAINING PROTEIN KINASE

ROCK1 is involved in the aggregation of platelets and the function of stress fibers and adhesions.

 

ROCK2 regulates cytokinesis, muscle contraction, and affects aqueous humor outflow.

 

PROTEIN KINASE ARGININE/SERINE RICH SPLICE FACTORS

SRPK1 phosphorylates serine-arginine rich proteins such as those of snRNPs.

 

SRPK2

 

SERUM-GLUCOSE-REGULATING KINASE

SGK changes transcription in hepatocytes based on the surrounding tonicity.  It is also expressed in kidneys.  Liver hepatocytes are depicted below.

LIVER CELLS

 SGKL is involved in membrane transport.

 

SNF1-LIKE KINASE is the homolog of the yeast kinase which acts on histone H3 after nutritional stress.

 

SERUM INDUCIBLE KINASE plays a role in cell cycle regulation.

 

TANK-BINDING KINASE 1; TBK1 is part of an antiviral response which increases the transcription of interferon.

 

TESTIS-SPECIFIC PROTEIN KINASES

TESK1 is expressed in spermatozoa and several other tissues including the brain.

 

TESK2 is expressed primarily in the testis and prostate.

 

TRANSFORMING GROWTH FACTOR RECEPTOR are serine/threonine kinases as opposed to the tyrosine kinases which compose most growth factor receptors.  These receptors function in cell proliferation and differentiation.  The TGFβ receptor family all possess a serine-threonine kinase.  Homologs are known in sponges, including genes which might be similar to ancestral genes of this family (Suga, 1999a).  TGFβ family is most closely related to raf and protein tyrosine kinase families (Suga, 1999a).

 

TGFBR1 is activated by TGFBR2 after TGFB1 has bound to it.

 

TGFBR2 mutations can cause colorectal and esophageal cancers.

 

TTK PROTEIN KINASE is a dual specificity kinase which regulates centrosome duplication.

 

UNC51-LIKE KINASE 1; ULK1 is ubiquitously expressed in humans, wit its highest expression in skeletal and cardiac muscle.  Its homolog in C. elegans is expressed only in neurons.

 

VACCINA RELATED KINASE; VRK1 is expressed to a greater extent in dividing cells.

 

CYCLIN DEPENDENT KINASES

    These kinases are discussed with the cyclins.

 

 

 

CAM KINASE 1 phosphorylates SYN1, CREB, and CFTR proteins

 

CAM KINASE 2A and 2B have identical functional domains and react with NMDA receptors.  Mutations in mice cause behavioral abnormalities and learning deficits.

 

Ca/CaM-dependent protein kinase is a serine/threonine kinase.  A number of invertebrates, ranging from sponges through protostomes and primitive deuterostomes, possess a single CamM kinase II gene.  Most vertebrates posses four genes (Tombes, 2003).  CaMKII are also related, as are MAPK enzymes, to eukaryotic initiation factor 2 α kinase and ribosomal protein S6 kinase (Suga, 1999a).

 

 

CAM KINASE 2D

 

CAM KINASE 2G

 

CAM KINASE IV is involved in transcription regulation in lymphocytes, neurons, and male germ cells.  It is also involved in learning.