MOD_NEK2_2
Accession: | |
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Functional site class: | NEK2 phosphorylation site |
Functional site description: | The NEK protein kinases are Never in mitosis A (NimA)-related kinases that belong to the NEK Serine/Threonine protein kinase family. NEKs have been identified in many Eukaryotes, where they play a critical role in cell cycle control. The closest mammalian NimA homologue NEK2 is a core component of the human centrosome and its activity and expression peak in S and G2 phase, during which it interacts with and phosphorylates several centrosomal proteins. NEK2 has many cell cycle-related functions, including cell cycle progression, spindle pole formation, microtubule anchoring, centriolar cohesion, cilia formation and chromatin condensation. |
ELMs with same func. site: | MOD_NEK2_1 MOD_NEK2_2 |
ELM Description: | The optimal substrate motif of NEK2 was determined by positional scanning oriented peptide library screening (PS-OPLS) (Alexander,2011). The substrate motif targeted by NEK2 for phosphorylation shows the strongest amino acid selectivity in the -3 and +2 positions (relative to the Ser/Thr residue that is phosphorylated by NEK2). Having a preferred residue in the -3 position might compensate for the occurrence of less favorable residues in the +1 and +2 positions and vice versa. To encode this information, two variants of the motif have been defined, based on the selectivity for particular residues observed in the PS-OPLS experiment (Alexander,2011). The second variant of the NEK2 substrate phosphorylation motif allows for a subset of hydrophobic amino acids, i.e. Pro, Tyr, Trp, Cys, Ala and Gly, in the -3 position. These residues are not as strongly selected as Phe, Leu or Met, but this might be compensated by selection of a subset of residues in the +1 and +2 positions in this second variant of the motif. Again, hydrophilic amino acids as well as Ile and Val are strongly disfavored in the -3 position. In the -2 position, all amino acids except Pro are tolerated, although there is a slight preference for basic and hydrophobic residues. Similarly, in the -1 position there is no strong selectivity except for a strong discrimination against Pro. Also in the +1 position Pro is disfavored, together with the acidic Glu and Asp residues. The strong selection against Pro in this position allows discrimination against Cdk1 mitotic kinase phosphorylation sites. In addition, there is a preference for a hydrophobic Ile, Phe, Cys, Val, Met or Leu residue in the +1 position. In the +2 position there is a strong preference for His, Arg, Lys, Tyr and Phe. Having one of these preferred residues in the +1 and +2 positions might compensate for the occurrence of a less favored residue in the -3 position as defined in this second variant of the motif. |
Pattern: | [WYPCAG][^P][^P]([ST])[IFCVML][KRHYF] |
Pattern Probability: | 0.0012950 |
Present in taxon: | Eukaryota |
Interaction Domain: |
Pkinase (PF00069)
Protein kinase domain
(Stochiometry: 1 : 1)
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NimA was initially identified in the filamentous fungus Aspergillus nidulans as a serine/threonine protein kinase vital for entry into mitosis (Oakley,1983). Kinases with structural and functional homology to NimA, known as NimA-related kinases (NEKs), have been identified throughout Eukaryotes, with higher Eukaryotes showing a significant expansion of the family. While a single NimA homologue exists in yeast, 2, 4 and 11 NimA-related kinases were identified in flies (D. melanogaster), worms (C. elegans) and Mammals, respectively (Moniz,2011). Of the human NEKs, NEK2 is most closely related to the fungal kinase. NEK2 is a cell cycle-regulated kinase with low activity in G1 phase, increased activity in S and G2 phase, and again diminished activity after mitotic onset. At the G1/S transition, the vertebrate NEK2 is expressed as two splice variants, NEK2A and NEK2B. Only the NEK2A variant contains the binding site necessary for substrate recognition, as well as a C-terminal destruction motif that mediates its APC/C dependent degradation. During interphase and early mitosis, NEK2 is localised to the centrosome, where it phosphorylates many of it substrates at serine/threonine residues. Either inhibition of NEK2 catalytic activity or knock down of its substrates, including cNap1, rootletin or beta-catenin, inhibits centrosome separation, spindle assembly and formation of multinucleated cells. In kinetochores, knock down of NEK2 causes the displacement of the centromeric protein Mad2 from kinetochores and impairs chromosome segregation (Moniz,2011). NEK2-catalysed phosphorylation of the spindle assembly checkpoint component Hec1 regulates kinetochore-microtubule binding (Fry,2012). These studies indicate that NEK2 may coordinate cell division at multiple levels, and that deregulation of NEK2 causes centrosome abnormalities and aneuploidy. Other studies have shown that NEK2 is associated with disease progression in non-Hodgkin lymphomas. |

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A centrosomal function for the human Nek2 protein kinase, a member of the NIMA family of cell cycle regulators.
Fry AM, Meraldi P, Nigg EA
EMBO J 1998 Feb 26; 17 (2), 470-81
PMID: 9430639
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C-Nap1, a novel centrosomal coiled-coil protein and candidate substrate of the cell cycle-regulated protein kinase Nek2.
Fry AM, Mayor T, Meraldi P, Stierhof YD, Tanaka K, Nigg EA
J Cell Biol 1998 Aug 03; 141 (7), 1563-74
PMID: 9647649
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NIMA-related kinase 2 (Nek2), a cell-cycle-regulated protein kinase localized to centrosomes, is complexed to protein phosphatase 1.
Helps NR, Luo X, Barker HM, Cohen PT
Biochem J 2001 Jan 26; 349 (2), 50918
PMID: 10880350
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The Nek2 protein kinase: a novel regulator of centrosome structure.
Fry AM
Oncogene 2002 Sep 05; 21 (40), 6184-94
PMID: 12214248
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Phosphorylation of the mitotic regulator protein Hec1 by Nek2 kinase is essential for faithful chromosome segregation.
Chen Y, Riley DJ, Zheng L, Chen PL, Lee WH
J Biol Chem 2002 Dec 16; 277 (51), 49408-16
PMID: 12386167
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Rootletin forms centriole-associated filaments and functions in centrosome cohesion.
Bahe S, Stierhof YD, Wilkinson CJ, Leiss F, Nigg EA
J Cell Biol 2005 Oct 11; 171 (1), 27-33
PMID: 16203858
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Structure and regulation of the human Nek2 centrosomal kinase.
Rellos P, Ivins FJ, Baxter JE, Pike A, Nott TJ, Parkinson DM, Das S, Howell S, Fedorov O, Shen QY, Fry AM, Knapp S, Smerdon SJ
J Biol Chem 2007 Feb 26; 282 (9), 6833-42
PMID: 17197699
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Characterization of NIP2/centrobin, a novel substrate of Nek2, and its potential role in microtubule stabilization.
Jeong Y, Lee J, Kim K, Yoo JC, Rhee K
J Cell Sci 2007 Jun 06; 120 (Pt 12), 2106-16
PMID: 17535851
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Phosphorylation of human Sgo1 by NEK2A is essential for chromosome congression in mitosis.
Fu G, Ding X, Yuan K, Aikhionbare F, Yao J, Cai X, Jiang K, Yao X
Cell Res 2007 Jul 16; 17 (7), 608-18
PMID: 17621308
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beta-Catenin is a Nek2 substrate involved in centrosome separation.
Bahmanyar S, Kaplan DD, Deluca JG, Giddings TH Jr, O'Toole ET, Winey M, Salmon ED, Casey PJ, Nelson WJ, Barth AI
Genes Dev 2008 Jan 03; 22 (1), 91-105
PMID: 18086858
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Nek2 targets the mitotic checkpoint proteins Mad2 and Cdc20: a mechanism for aneuploidy in cancer.
Liu Q, Hirohashi Y, Du X, Greene MI, Wang Q
Exp Mol Pathol 2010 Apr 02; 88 (2), 225-33
PMID: 20034488
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Spatial exclusivity combined with positive and negative selection of phosphorylation motifs is the basis for context-dependent mitotic signaling.
Alexander J, Lim D, Joughin BA, Hegemann B, Hutchins JR, Ehrenberger T, Ivins F, Sessa F, Hudecz O, Nigg EA, Fry AM, Musacchio A, Stukenberg PT, Mechtler K, Peters JM, Smerdon SJ, Yaffe MB
Sci Signal 2011 Jun 29; 4 (179), ra42
PMID: 21712545

Please cite:
The Eukaryotic Linear Motif resource: 2022 release.
(PMID:34718738)
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement