PIM1

PIM1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1XQZ, 1XR1, 1XWS, 1YHS, 1YI3, 1YI4, 1YWV, 1YXS, 1YXT, 1YXU, 1YXV, 1YXX, 2BIK, 2BIL, 2BZH, 2BZI, 2BZJ, 2BZK, 2C3I, 2J2I, 2O3P, 2O63, 2O64, 2O65, 2OBJ, 2OI4, 2XIX, 2XIY, 2XIZ, 2XJ0, 2XJ1, 2XJ2, 3A99, 3BGP, 3BGQ, 3BGZ, 3BWF, 3C4E, 3CXW, 3CY2, 3CY3, 3DCV, 3F2A, 3JPV, 3JXW, 3JY0, 3JYA, 3MA3, 3QF9, 3R00, 3R01, 3R02, 3R04, 3T9I, 3UIX, 3UMW, 3UMX, 3VBQ, 3VBT, 3VBV, 3VBW, 3VBX, 3VBY, 3VC4, 3WE8, 4A7C, 4ALU, 4ALV, 4ALW, 4AS0, 4BZN, 4BZO, 4DTK, 4ENX, 4ENY, 4GW8, 4I41, 4IAA, 4JX3, 4JX7, 4K0Y, 4K18, 4K1B, 4LL5, 4LM5, 4MBI, 4MBL, 4MED, 4MTA, 4N6Y, 4N6Z, 4N70, 4RBL, 4RC2, 4RC3, 4RC4, 4RPV, 4TY1, 4WRS, 4WSY, 4WT6, 4XHK, 4XH6, 5C1Q, 5DWR, 5DIA, 5DHJ, 5DGZ, 5EOL, 5IPJ, 5IIS
Identifiers
Aliases	PIM1, PIM, Pim-1 proto-oncogene, serine/threonine kinase
External IDs	MGI: 97584 HomoloGene: 11214 GeneCards: PIM1
Targeted by Drug
ruboxistaurin[1]
Gene ontology Molecular function • transferase activity • nucleotide binding • protein kinase activity • manganese ion binding • ribosomal small subunit binding • transcription factor binding • metal ion binding • kinase activity • protein serine/threonine kinase activity • protein binding • ATP binding Cellular component • cytoplasm • membrane • plasma membrane • nucleus Biological process • positive regulation of cyclin-dependent protein serine/threonine kinase activity involved in G1/S transition of mitotic cell cycle • phosphorylation • negative regulation of apoptotic process • negative regulation of sequence-specific DNA binding transcription factor activity • multicellular organism development • protein phosphorylation • hyaluronan metabolic process • protein autophosphorylation • cell cycle • cell proliferation • vitamin D receptor signaling pathway • apoptotic process Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5292	18712
Ensembl	ENSG00000137193	ENSMUSG00000024014
UniProt	P11309	P06803
RefSeq (mRNA)	NM_002648 NM_001243186	NM_008842
RefSeq (protein)	NP_001230115.1 NP_002639.1	n/a
Location (UCSC)	Chr 6: 37.17 – 37.18 Mb	Chr 17: 29.49 – 29.5 Mb
PubMed search	[2]	[3]
Wikidata

Proto-oncogene serine/threonine-protein kinase Pim-1 is an enzyme that in humans is encoded by the PIM1 gene.^[4][5][6]

Pim-1 is a proto-oncogene which encodes for the serine/threonine kinase of the same name. The pim-1 oncogene was first described in relation to murine T-cell lymphomas, as it was the locus most frequently activated by the Moloney murine leukemia virus.^[7] Subsequently, the oncogene has been implicated in multiple human cancers, including prostate cancer, acute myeloid leukemia and other hematopoietic malignancies.^[8] Primarily expressed in spleen, thymus, bone marrow, prostate, oral epithelial, hippocampus and fetal liver cells, Pim-1 has also been found to be highly expressed in cell cultures isolated from human tumors.^[7] Pim-1 is mainly involved in cell cycle progression, apoptosis and transcriptional activation, as well as more general signal transduction pathways.^[7]

Gene

Located on chromosome 6 (6p21.2), the gene encompasses 5Kb of DNA, including 6 exons and 5 introns. Expression of Pim-1 has been shown to be regulated by the JAK/STAT pathway. Direct binding of transcription factors STAT3 and STAT5 to the Pim-1 promoter results in the transcription of Pim-1.^[7] The Pim-1 gene has been found to be conserved in dogs, cows, mice, rats, zebrafish and C. elegans. Pim-1 deficient mice have been shown to be phenotypically normal, indicating that there is redundancy in the function of this kinase.^[7] In fact, sequence homology searches have shown that two other Pim-1-like kinases, Pim-2 and Pim-3, are structurally and functionally similar.^[7] The Pim-1 gene encodes has multiple translation initiation sites, resulting in two proteins of 34 and 44kD.^[7]

Protein structure

Human, murine and rat Pim-1 contain 313 amino acids, and have a 94 – 97% amino acid identity.^[7] The active site of the protein, ranging from amino acids 38-290, is composed of several conserved motifs, including a glycine loop motif, a phosphate binding site and a proton acceptor site.^[7] Modification of the protein at amino acid 67 (lysine to methionine) results in the inactivation of the kinase.^[7]

Activation and stabilization

Pim-1 is primarily involved in cytokine signaling, and has been implicated in many signal transduction pathways. Because Pim-1 transcription is initiated by STAT3 and STAT5, its production is regulated by the cytokines that regulate the STAT pathway, or STAT factors. These include interleukins (IL-2, IL-3,IL-5, IL-6, IL-7, IL12, IL-15), prolactin, TNFα, EGF and IFNγ, among others.^[7] Pim-1 itself can bind to negative regulators of the JAK/STAT pathway, resulting in a negative feedback loop.

Although little is known about the post-transcriptional modifications of Pim-1, it has been hypothesized that Hsp90 is responsible for the folding and stabilization of Pim-1, although the exact mechanism has yet to be discovered.^[7] Furthermore, the serine/threonine phosphatase PP2 has been shown to degrade Pim-1.

Interactions

PIM1 has been shown to interact with:

• CBX3,^[9]
• CDC25A,^[10]
• Heat shock protein 90kDa alpha (cytosolic), member A1,^[11]
• NFATC1,^[12]
• Nuclear mitotic apparatus protein 1,^[13]
• P21,^[14]
• SND1^[15] and
• RELA.^[16]

Other known substrates/binding partners of Pim-1 include proteins involved in transcription regulation (nuclear adaptor protein p100, HP-1, PAP-1 and TRAF2 / SNX6), and regulation of the JAK/STAT pathway (SOCS1 and SOCS3).^[7] Furthermore, Pim-1 has been shown to be a cofactor for c-Myc, a transcription factor believed to regulate 15% of all genes, and their synergy has been in prostate tumorigenesis.^[17]

Pim-1 is able to phosphorylate many targets, including itself. Many of its targets are involved in cell cycle regulation.

Activates

• Cdc25C (G₁/S positive regulator): Activation results in increased G₁ → S^[7]
• Cdc25C (G₂/M positive regulator): Activation results in increased G₂ → M^[7]

Deactivates

• Bad (Pro-apoptotic protein): Deactivation results in increased cell survival^[7]
• CKI (G1/S negative regulator): Deactivation results in increased G₁ → S^[7]
• C-TAK1 (Cdc25C inhibitor): Deactivation results in increased G₂ → M^[7]

Clinical implications

Pim-1 is directly involved in the regulation of cell cycle progression and apoptosis, and has been implicated in numerous cancers including prostate cancer, Burkitt’s lymphoma and oral cancer, as well as numerous hematopoietic lymphomas. Single nucleotide polymorphisms in the Pim-1 gene have been associated with increased risk for lung cancer in Korean patients, and have also been found in diffuse large cell lymphomas.^[18] As well as showing useful activity against a range of cancers, PIM kinase inhibitors have also been suggested as possible treatments for Alzheimer's disease.^[19]

Inhibitors

A large number of small molecule inhibitors of PIM1 have been developed. Clinical trial results so far have showed promising anti-cancer activity, but side effects due to insufficient selectivity have proved problematic and research continues to find more potent and selective inhibitors for this target.^{[20][21][22][23][24][25][26]}

Examples

• AZD1208
• LGH447
• SGI-1776
• TP-3654

References

Further reading

PDB gallery
1xqz: Crystal Structure of hPim-1 kinase at 2.1 A resolution  1xr1: Crystal structure of hPim-1 kinase in complex with AMP-PNP at 2.1 A Resolution  1xws: Crystal Structure of the human PIM1 kinase domain  1yhs: Crystal structure of Pim-1 bound to staurosporine  1yi3: Crystal Structure of Pim-1 bound to LY294002  1yi4: Structure of Pim-1 bound to adenosine  1ywv: Crystal Structures of Proto-Oncogene Kinase Pim1: a Target of Aberrant Somatic Hypermutations in Diffuse Large Cell Lymphoma  1yxs: Crystal Structure of Kinase Pim1 with P123M mutation  1yxt: Crystal Structure of Kinase Pim1 in complex with AMPPNP  1yxu: Crystal Structure of Kinase Pim1 in Complex with AMP  1yxv: Crystal Structure of Kinase Pim1 in complex with 3,4-Dihydroxy-1-methylquinolin-2(1H)-one  1yxx: Crystal Structure of Kinase Pim1 in complex with (3E)-3-[(4-HYDROXYPHENYL)IMINO]-1H-INDOL-2(3H)-ONE  2bik: HUMAN PIM1 PHOSPHORYLATED ON SER261  2bil: THE HUMAN PROTEIN KINASE PIM1 IN COMPLEX WITH ITS CONSENSUS PEPTIDE PIMTIDE  2bzh: CRYSTAL STRUCTURE OF THE HUMAN PIM1 IN COMPLEX WITH A RUTHENIUM ORGANOMETALLIC LIGAND RU1  2bzi: CRYSTAL STRUCTURE OF THE HUMAN PIM1 IN COMPLEX WITH A RUTHENIUM ORGANOMETALLIC LIGAND RU2  2bzj: CRYSTAL STRUCTURE OF THE HUMAN PIM1 IN COMPLEX WITH A RUTHENIUM ORGANOMETALLIC LIGAND RU3  2bzk: CRYSTAL STRUCTURE OF THE HUMAN PIM1 IN COMPLEX WITH AMPPNP AND PIMTIDE  2c3i: CRYSTAL STRUCTURE OF HUMAN PIM1 IN COMPLEX WITH IMIDAZOPYRIDAZIN I  2j2i: CRYSTAL STRUCTURE OF THE HUMAB PIM1 IN COMPLEX WITH LY333531  2o3p: Crystal structure of Pim1 with Quercetin  2o63: Crystal structure of Pim1 with Myricetin  2o64: Crystal structure of Pim1 with Quercetagetin  2o65: Crystal structure of Pim1 with Pentahydroxyflavone  2obj: Crystal structure of human PIM-1 Kinase in complex with inhibitor  2oi4: Crystal structure of human PIM1 in complex with fluorinated ruthenium pyridocarbazole