Serine/threonine-protein kinase pim-1

Details

Name
Serine/threonine-protein kinase pim-1
Synonyms
  • 2.7.11.1
Gene Name
PIM1
Organism
Humans
Amino acid sequence
>lcl|BSEQ0002541|Serine/threonine-protein kinase pim-1
MPHEPHEPLTPPFSALPDPAGAPSRRQSRQRPQLSSDSPSAFRASRSHSRNATRSHSHSH
SPRHSLRHSPGSGSCGSSSGHRPCADILEVGMLLSKINSLAHLRAAPCNDLHATKLAPGK
EKEPLESQYQVGPLLGSGGFGSVYSGIRVSDNLPVAIKHVEKDRISDWGELPNGTRVPME
VVLLKKVSSGFSGVIRLLDWFERPDSFVLILERPEPVQDLFDFITERGALQEELARSFFW
QVLEAVRHCHNCGVLHRDIKDENILIDLNRGELKLIDFGSGALLKDTVYTDFDGTRVYSP
PEWIRYHRYHGRSAAVWSLGILLYDMVCGDIPFEHDEEIIRGQVFFRQRVSSECQHLIRW
CLALRPSDRPTFEEIQNHPWMQDVLLPQETAEIHLHSLSPGPSK
Number of residues
404
Molecular Weight
45411.905
Theoretical pI
7.01
GO Classification
Functions
ATP binding / manganese ion binding / protein serine/threonine kinase activity / ribosomal small subunit binding / transcription factor binding
Processes
apoptotic process / cell cycle / cell proliferation / hyaluronan metabolic process / multicellular organismal development / negative regulation of apoptotic process / negative regulation of sequence-specific DNA binding transcription factor activity / positive regulation of cyclin-dependent protein serine/threonine kinase activity involved in G1/S transition of mitotic cell cycle / protein autophosphorylation / protein phosphorylation / regulation of mitotic cell cycle / vitamin D receptor signaling pathway
Components
cytoplasm / nucleus / plasma membrane
General Function
Transcription factor binding
Specific Function
Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post-translational levels. Phosphorylation of CDKN1B,induces 14-3-3-proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis.
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Cytoplasm
Gene sequence
>lcl|BSEQ0010889|Serine/threonine-protein kinase pim-1 (PIM1)
CTGCCGCACGAGCCCCACGAGCCGCTCACCCCGCCGTTCTCAGCGCTGCCCGACCCCGCT
GGCGCGCCCTCCCGCCGCCAGTCCCGGCAGCGCCCTCAGTTGTCCTCCGACTCGCCCTCG
GCCTTCCGCGCCAGCCGCAGCCACAGCCGCAACGCCACCCGCAGCCACAGCCACAGCCAC
AGCCCCAGGCATAGCCTTCGGCACAGCCCCGGCTCCGGCTCCTGCGGCAGCTCCTCTGGG
CACCGTCCCTGCGCCGACATCCTGGAGGTTGGGATGCTCTTGTCCAAAATCAACTCGCTT
GCCCACCTGCGCGCCGCGCCCTGCAACGACCTGCACGCCACCAAGCTGGCGCCCGGCAAG
GAGAAGGAGCCCCTGGAGTCGCAGTACCAGGTGGGCCCGCTACTGGGCAGCGGCGGCTTC
GGCTCGGTCTACTCAGGCATCCGCGTCTCCGACAACTTGCCGGTGGCCATCAAACACGTG
GAGAAGGACCGGATTTCCGACTGGGGAGAGCTGCCTAATGGCACTCGAGTGCCCATGGAA
GTGGTCCTGCTGAAGAAGGTGAGCTCGGGTTTCTCCGGCGTCATTAGGCTCCTGGACTGG
TTCGAGAGGCCCGACAGTTTCGTCCTGATCCTGGAGAGGCCCGAGCCGGTGCAAGATCTC
TTCGACTTCATCACGGAAAGGGGAGCCCTGCAAGAGGAGCTGGCCCGCAGCTTCTTCTGG
CAGGTGCTGGAGGCCGTGCGGCACTGCCACAACTGCGGGGTGCTCCACCGCGACATCAAG
GACGAAAACATCCTTATCGACCTCAATCGCGGCGAGCTCAAGCTCATCGACTTCGGGTCG
GGGGCGCTGCTCAAGGACACCGTCTACACGGACTTCGATGGGACCCGAGTGTATAGCCCT
CCAGAGTGGATCCGCTACCATCGCTACCATGGCAGGTCGGCGGCAGTCTGGTCCCTGGGG
ATCCTGCTGTATGATATGGTGTGTGGAGATATTCCTTTCGAGCATGACGAAGAGATCATC
AGGGGCCAGGTTTTCTTCAGGCAGAGGGTCTCTTCAGAATGTCAGCATCTCATTAGATGG
TGCTTGGCCCTGAGACCATCAGATAGGCCAACCTTCGAAGAAATCCAGAACCATCCATGG
ATGCAAGATGTTCTCCTGCCCCAGGAAACTGCTGAGATCCACCTCCACAGCCTGTCGCCG
GGGCCCAGCAAATAG
Chromosome Location
6
Locus
6p21.2
External Identifiers
ResourceLink
UniProtKB IDP11309
UniProtKB Entry NamePIM1_HUMAN
GenBank Protein ID387022
GenBank Gene IDM27903
GenAtlas IDPIM1
HGNC IDHGNC:8986
General References
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  2. Zakut-Houri R, Hazum S, Givol D, Telerman A: The cDNA sequence and gene analysis of the human pim oncogene. Gene. 1987;54(1):105-11. [PubMed:3475233]
  3. Domen J, Von Lindern M, Hermans A, Breuer M, Grosveld G, Berns A: Comparison of the human and mouse PIM-1 cDNAs: nucleotide sequence and immunological identification of the in vitro synthesized PIM-1 protein. Oncogene Res. 1987 Jun;1(1):103-12. [PubMed:3329709]
  4. Meeker TC, Nagarajan L, ar-Rushdi A, Croce CM: Cloning and characterization of the human PIM-1 gene: a putative oncogene related to the protein kinases. J Cell Biochem. 1987 Oct;35(2):105-12. [PubMed:3429489]
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  8. Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, Kuppers R, Dalla-Favera R: Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature. 2001 Jul 19;412(6844):341-6. [PubMed:11460166]
  9. Telerman A, Amson R, Zakut-Houri R, Givol D: Identification of the human pim-1 gene product as a 33-kilodalton cytoplasmic protein with tyrosine kinase activity. Mol Cell Biol. 1988 Apr;8(4):1498-503. [PubMed:2837645]
  10. Saris CJ, Domen J, Berns A: The pim-1 oncogene encodes two related protein-serine/threonine kinases by alternative initiation at AUG and CUG. EMBO J. 1991 Mar;10(3):655-64. [PubMed:1825810]
  11. Koike N, Maita H, Taira T, Ariga H, Iguchi-Ariga SM: Identification of heterochromatin protein 1 (HP1) as a phosphorylation target by Pim-1 kinase and the effect of phosphorylation on the transcriptional repression function of HP1(1). FEBS Lett. 2000 Feb 4;467(1):17-21. [PubMed:10664448]
  12. Wang Z, Bhattacharya N, Mixter PF, Wei W, Sedivy J, Magnuson NS: Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase. Biochim Biophys Acta. 2002 Dec 16;1593(1):45-55. [PubMed:12431783]
  13. Ionov Y, Le X, Tunquist BJ, Sweetenham J, Sachs T, Ryder J, Johnson T, Lilly MB, Kraft AS: Pim-1 protein kinase is nuclear in Burkitt's lymphoma: nuclear localization is necessary for its biologic effects. Anticancer Res. 2003 Jan-Feb;23(1A):167-78. [PubMed:12680209]
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  15. Stout BA, Bates ME, Liu LY, Farrington NN, Bertics PJ: IL-5 and granulocyte-macrophage colony-stimulating factor activate STAT3 and STAT5 and promote Pim-1 and cyclin D3 protein expression in human eosinophils. J Immunol. 2004 Nov 15;173(10):6409-17. [PubMed:15528381]
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  17. Bachmann M, Kosan C, Xing PX, Montenarh M, Hoffmann I, Moroy T: The oncogenic serine/threonine kinase Pim-1 directly phosphorylates and activates the G2/M specific phosphatase Cdc25C. Int J Biochem Cell Biol. 2006 Mar;38(3):430-43. Epub 2005 Nov 8. [PubMed:16356754]
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  19. Gu JJ, Wang Z, Reeves R, Magnuson NS: PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis. Oncogene. 2009 Dec 3;28(48):4261-71. doi: 10.1038/onc.2009.276. Epub 2009 Sep 14. [PubMed:19749799]
  20. Jacobs MD, Black J, Futer O, Swenson L, Hare B, Fleming M, Saxena K: Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002. J Biol Chem. 2005 Apr 8;280(14):13728-34. Epub 2005 Jan 17. [PubMed:15657054]
  21. Qian KC, Wang L, Hickey ER, Studts J, Barringer K, Peng C, Kronkaitis A, Li J, White A, Mische S, Farmer B: Structural basis of constitutive activity and a unique nucleotide binding mode of human Pim-1 kinase. J Biol Chem. 2005 Feb 18;280(7):6130-7. Epub 2004 Nov 3. [PubMed:15525646]
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Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB017543,4-Dihydroxy-1-Methylquinolin-2(1h)-OneexperimentalunknownDetails
DB00131Adenosine phosphateapproved, investigational, nutraceuticalunknownproduct ofDetails
DB02010StaurosporineexperimentalunknownDetails
DB02656LY-294002experimentalunknownDetails
DB03366Imidazoleexperimental, investigationalunknownDetails
DB03650(3e)-3-[(4-Hydroxyphenyl)Imino]-1h-Indol-2(3h)-OneexperimentalunknownDetails
DB03777Rbt205 InhibitorexperimentalunknownDetails
DB04395Phosphoaminophosphonic Acid-Adenylate EsterexperimentalunknownDetails
DB04522DexfosfoserineexperimentalunknownDetails
DB04530S,S-(2-Hydroxyethyl)ThiocysteineexperimentalunknownDetails
DB04715IMIDAZOPYRIDAZIN 1experimentalunknownDetails
DB071514-(4-hydroxy-3-methylphenyl)-6-phenylpyrimidin-2(5H)-oneexperimentalunknownDetails
DB07524N-phenyl-1H-pyrrolo[2,3-b]pyridin-3-amineexperimentalunknownDetails
DB08022(2S)-1,3-benzothiazol-2-yl{2-[(2-pyridin-3-ylethyl)amino]pyrimidin-4-yl}ethanenitrileexperimentalunknownDetails
DB07242(4R)-7,8-dichloro-1',9-dimethyl-1-oxo-1,2,4,9-tetrahydrospiro[beta-carboline-3,4'-piperidine]-4-carbonitrileexperimentalunknownDetails
DB08166(4R)-7-chloro-9-methyl-1-oxo-1,2,4,9-tetrahydrospiro[beta-carboline-3,4'-piperidine]-4-carbonitrileexperimentalunknownDetails
DB082305,7-DIHYDROXY-2-(3,4,5-TRIHYDROXYPHENYL)-4H-CHROMEN-4-ONEexperimentalunknownDetails
DB04216Quercetinexperimental, investigationalunknownDetails
DB087056-(5-BROMO-2-HYDROXYPHENYL)-2-OXO-4-PHENYL-1,2-DIHYDROPYRIDINE-3-CARBONITRILEexperimentalunknownDetails
DB087074-[3-(4-chlorophenyl)-2,1-benzisoxazol-5-yl]pyrimidin-2-amineexperimentalunknownDetails
DB08708N-cyclohexyl-3-[3-(trifluoromethyl)phenyl][1,2,4]triazolo[4,3-b]pyridazin-6-amineexperimentalunknownDetails
DB087092,3-diphenyl-1H-indole-7-carboxylic acidexperimentalunknownDetails
DB12010Fostamatinibapproved, investigationalunknowninhibitorDetails