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Gene Review

Uhmk1  -  U2AF homology motif (UHM) kinase 1

Rattus norvegicus

Synonyms: KIS, Kinase interacting with stathmin, Kis, Kist, P-CIP2, ...
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Disease relevance of Uhmk1

  • The antiestrogen ICI 164384 as well as tamoxifen and its metabolites inhibit estrone sulfatase via noncompetitive mechanisms at Kis ranging from 11-1130 microM in rat breast tumors [1].
  • Kis measured 6 h after a 10 min period of normothermic forebrain ischemia were increased to 4.0-6.2 (reagents) and 6.6-7.5 (sucrose) in two brain regions, striatum and hippocampus, known to be especially vulnerable to ischemic injury [2].

High impact information on Uhmk1

  • Ouabain inhibition curves of Na,K-ATPase were monophasic with Kis of 2.6 +/- 1.4 x 10(-4) and 2.0 +/- 1.2 x 10(-4) M for control and diabetic rats, respectively (NS) [3].
  • The inhibitory effects of L-MTX and its optical isomer, (-) amethopterin (D-MTX), on the uptake of [3H]L-MTX differed with Kis of 326 and 93 microM, respectively, indicating that the biologically inactive D form has a higher affinity for cMOAT than L-MTX [4].
  • However, quisqualate displacement of [3H]glutamate binding revealed two well-resolved sites with KIS of 12 nM and 114 microM in striatum [5].
  • Three PAM cytosolic interactor proteins (P-CIPs) were identified using the yeast two hybrid system (Alam, M. R., Caldwel, B. D., Johnson, R. C., Darlington, D. N., Mains, R. E., and Eipper, B. A. (1996) J. Biol. Chem. 271, 28636-28640); the partial amino acid sequence of P-CIP2 suggested that it was a protein kinase [6].
  • P-CIP2 was homologous to several serine/threonine and dual specificity protein kinases, while P-CIP10 contained spectrin-like repeats [7].

Biological context of Uhmk1


Anatomical context of Uhmk1

  • The Kis obtained with synaptosomes are in good agreement with the Ki values obtained from electrophysiological experiments at the frog neuromuscular junction (KPb:0.99 microM, KCd: 1.7 microM)7 [12].
  • Measurements of BBB permeability to DyTTHA3- after osmotic opening of the barrier with hypertonic arabinose gave Kis of 25-30 in forebrain regions [2].
  • The log IC50s of the muscarinic receptor agonists for decreasing twitch-height were highly correlated with their log Kis for inhibiting [3H]pirenzepine (r = 0.96) and [3H]oxotremorine-M (r = 0.85) binding in rat hippocampal membranes [13].
  • A sensitive radiotracer technique was used to measure transfer constants (Kis) for blood to brain diffusion of the MR contrast reagent gadolinium diethylenetriaminepentaacetate (GdDTPA2-) and the MR shift reagent dysprosium triethylenetetraminehexaacetate (DyTTHA3-) across the normal and the ischemically injured blood-brain barrier (BBB) of rats [2].
  • In the post-ischemic rats, Kis for both tracers were elevated significantly (P < 0.01) in parietal cortex, striatum, hippocampus, and midbrain [14].

Associations of Uhmk1 with chemical compounds

  • Further analysis indicates mixed non-competitive type inhibition by methadone with inhibition constants (Kis and Kii, respectively) of 0.03 +/- 0.01 (SE) and 0.57 +/- 0.12 microM [15].
  • Methadone and tramadol inhibited synaptosomal [3H]-5-HT uptake with apparent Kis of 0.27 +/- 0.04 and 0.76 +/- 0.04 microM, respectively [16].
  • Additionally, several typical antipsychotic drugs had high affinities for the cloned rat D4 receptor, with Kis less than 20 nM (loxapine, chlorpromazine, fluphenazine, mesoridazine, thioridazine and trifluoroperazine) [17].
  • Clozapine and several related atypical antipsychotic agents (rilapine, olanzepine, tiospirone, fluperlapine, clorotepine and zotepine) had high affinities for the newly discovered 5-HT6 receptor (Kis < 20 nM) [18].
  • The drugs Ro 5-4864, diazepam and flunitrazepam were potent inhibitors of this binding (Kis of 10(-9)-10(-8) M) whereas clonazepam, CL 218,872 and Ro 15-1788 were weak inhibitors (Kis greater than 10(-5) M) [19].

Analytical, diagnostic and therapeutic context of Uhmk1

  • Site-directed mutagenesis, phosphoamino acid analysis, and use of synthetic peptides demonstrate that PAM-Ser(949) is the major site phosphorylated by P-CIP2 [6].
  • Based on both in vitro binding experiments and co-immunoprecipitation from cell extracts, P-CIP2 interacts with PAM proteins containing the wild type cytosolic domain, but not with mutant forms of PAM whose trafficking is disrupted [6].
  • The targets chosen were a protein kinase, P-CIP2, for mRNA assessment and its downsteam target, peptidylglycine amidating monoxygenase (PAM), for immunohistochemistry (IHC) [20].


  1. Inhibition of estrone sulfatase and 17 beta-hydroxysteroid dehydrogenase by antiestrogens. Santner, S.J., Santen, R.J. J. Steroid Biochem. Mol. Biol. (1993) [Pubmed]
  2. Diffusion into rat brain of contrast and shift reagents for magnetic resonance imaging and spectroscopy. Preston, E., Foster, D.O. NMR in biomedicine. (1993) [Pubmed]
  3. Na,K-ATPase in diabetic rat small intestine. Changes at protein and mRNA levels and role of glucagon. Barada, K., Okolo, C., Field, M., Cortas, N. J. Clin. Invest. (1994) [Pubmed]
  4. Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats. Masuda, M., I'izuka, Y., Yamazaki, M., Nishigaki, R., Kato, Y., Ni'inuma, K., Suzuki, H., Sugiyama, Y. Cancer Res. (1997) [Pubmed]
  5. Quantitative autoradiographic distribution of L-[3H]glutamate-binding sites in rat central nervous system. Greenamyre, J.T., Young, A.B., Penney, J.B. J. Neurosci. (1984) [Pubmed]
  6. The novel kinase peptidylglycine alpha-amidating monooxygenase cytosolic interactor protein 2 interacts with the cytosolic routing determinants of the peptide processing enzyme peptidylglycine alpha-amidating monooxygenase. Caldwell, B.D., Darlington, D.N., Penzes, P., Johnson, R.C., Eipper, B.A., Mains, R.E. J. Biol. Chem. (1999) [Pubmed]
  7. Novel proteins that interact with the COOH-terminal cytosolic routing determinants of an integral membrane peptide-processing enzyme. Alam, M.R., Caldwell, B.D., Johnson, R.C., Darlington, D.N., Mains, R.E., Eipper, B.A. J. Biol. Chem. (1996) [Pubmed]
  8. Cytoplasmic 5'-nucleotidase catalyzes acyclovir phosphorylation. Keller, P.M., McKee, S.A., Fyfe, J.A. J. Biol. Chem. (1985) [Pubmed]
  9. Pharmacological comparison of two corticotropin-releasing factor antagonists: in vivo and in vitro studies. Curtis, A.L., Grigoriadis, D.E., Page, M.E., Rivier, J., Valentino, R.J. J. Pharmacol. Exp. Ther. (1994) [Pubmed]
  10. Specific binding of [3H]L-glutamate to cerebellar membranes: evidence for recognition site heterogeneity. Slevin, J., Collins, J., Lindsley, K., Coyle, J.T. Brain Res. (1982) [Pubmed]
  11. Characterization of pirenzepine interaction with cytochrome P-450. Rendić, S., Ruf, H.H. Xenobiotica (1985) [Pubmed]
  12. Effects of Pb2+ and Cd2+ on acetylcholine release and Ca2+ movements in synaptosomes and subcellular fractions from rat brain and Torpedo electric organ. Suszkiw, J., Toth, G., Murawsky, M., Cooper, G.P. Brain Res. (1984) [Pubmed]
  13. Muscarinic M1 receptor agonist actions of muscarinic receptor agonists in rabbit vas deferens. Shannon, H.E., Sawyer, B.D., Bemis, K.G., Bymaster, F.P., Health, I., Mitch, C.H., Ward, J.S. Eur. J. Pharmacol. (1993) [Pubmed]
  14. Evidence for pore-like opening of the blood-brain barrier following forebrain ischemia in rats. Preston, E., Foster, D.O. Brain Res. (1997) [Pubmed]
  15. Methadone: a potent inhibitor of rat liver aldehyde oxidase. Robertson, I.G., Gamage, R.S. Biochem. Pharmacol. (1994) [Pubmed]
  16. Effect of acute and chronic tramadol on [3H]-5-HT uptake in rat cortical synaptosomes. Giusti, P., Buriani, A., Cima, L., Lipartiti, M. Br. J. Pharmacol. (1997) [Pubmed]
  17. D4 dopamine receptor binding affinity does not distinguish between typical and atypical antipsychotic drugs. Roth, B.L., Tandra, S., Burgess, L.H., Sibley, D.R., Meltzer, H.Y. Psychopharmacology (Berl.) (1995) [Pubmed]
  18. Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors. Roth, B.L., Craigo, S.C., Choudhary, M.S., Uluer, A., Monsma, F.J., Shen, Y., Meltzer, H.Y., Sibley, D.R. J. Pharmacol. Exp. Ther. (1994) [Pubmed]
  19. Characterization of peripheral-type benzodiazepine recognition sites in the rat spinal cord. Villiger, J.W. Neuropharmacology (1985) [Pubmed]
  20. A pilot evaluation of the use of tissue microarrays for quantitation of target distribution in drug discovery pathology. McKay, J.S., Bigley, A., Bell, A., Jenkins, R., Somers, R., Brocklehurst, S., White, A., Goodwin, L. Experimental and toxicologic pathology : official journal of the Gesellschaft für Toxikologische Pathologie. (2006) [Pubmed]
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