NEKs

The Nek protein kinase subfamily is named after the NIMA protein kinase of Aspergillus nidulans.  Loss of NIMA function results in arrest at the G2/M boundary of the cell cycle despite activation of Cdc2. NIMA is necessary for the nuclear import of Cdc2 at the start of mitosis, and also for the construction of the mitotic spindle. Overexpression of NIMA results in chromatin condensation (possibly through direct histone H3 phosphorylation), and pseudomitotic arrest in both Aspergillus (where it also induces abnormal spindles) and in mammalian cells. The latter suggested that a NIMA-like signaling pathway exists in higher eukaryotes. A single NIMA-family member has been described in both budding and fission yeast, named KIN3 and fin-1, respectively; the latter has been shown to be involved in the control of late mitotic events. The human genome encodes 11 protein kinases whose catalytic domains are approximately 40% identical to NIMA, and 40-85% identical to each other. Research in the past 10 years indicates that the expansion of the Nek family may reflect both an enlargement and a subdivision of the functions of NIMA among a divergent array of related kinases.

The Nek protein kinase domains are all located near the protein aminoterminus (except for a central location in Nek10). Neks differ primarily in their noncatalytic carboxyterminal tails, which presumably specify different cellular localizations, substrate selection and/or modes of regulation. A feature common to the noncatalytic regions of almost all Neks is the presence of one or more coiled-coil motifs, that in at least two cases (Nek2 and Nercc1/Nek9) confer a homo-oligomerization that is essential to the activation of their catalytic function. In addition, Nek8 and Nercc1 contain a domain homologous to RCC1, the guanyl nucleotide exchange factor for the small GTPase Ran. In the case of Nercc1 the RCC1 domain acts as an autoinhibitory domain that is capable of binding both the Nercc1 catalytic domain and Ran.

Little is known as to the regulation or functions of Nek3, Nek4, Nek5 and Nek10. Nek2 is predominantly a centrosomal protein whose kinase activity is high in S and G2, wherein it is involved in centrosome separation, and low in M and G1. Nercc1/Nek9 is activated in mitosis, and is necessary for proper organization of the mitotic spindle. Microinjection of anti-Nercc1 antibodies during prophase induces arrest in prometaphase with disorganized spindle structures or abnormal mitosis with resultant aneuploidy. Nek6 and Nek7, 85% identical, lack appreciable noncatalytic segments; Nek6 and Nek7 bind to the carboxyterminal tail of Nercc1 and can be phosphorylated and activated by the latter both in vivo and in vitro, likely forming a signaling cassette that is activated during mitosis. Interference with, or RNAi-induced depletion of Nek 6, impedes mitotic progression.

Nek1 and Nek8 are unrelated in their carboxyterminal noncatalytic tails, however mutations in the genes encoding these polypeptides have been identified as the causative lesion in two mouse models of autosomal recessive polycystic kidney disease (PKD). Gene products identified whose mutation results in PKD have been shown to be localized to the non-motile cilia of renal epithelia. Fa2p, a Nek ortholog in Chlamydomonas is important for ciliary function and Nek1 and Nek8 are localized to some extent to the primary cilia of different cell types. It is likely therefore that Nek1 and Nek8 are also involved in the formation or function of cilia. In addition Nek1, Nek2 and Nek11 have been suggested to be involved in the response to DNA damage.

Neks differ in size, expression pattern, subcellular localization and protein kinase activity regulation. Nevertheless, the pattern from reports indicates that one important, common function of several Neks is in the control of the centrosomal and cellular microtubule machinery. Thus, some Neks may retain important roles related to those of NIMA in the regulation of centrosome and/or spindle structure and function and perhaps other cell cycle-related processes (such the response to DNA damage), while other Neks may have evolved to participate in the regulation of other highly specialized microtubule structures such as cilia.

The Table below contains accepted modulators and additional information.

 

Family Members Nek1
(SRP5329)
Nek2
(N4787, SRP0357)
Nek3
(SRP5052)
Nek4 Nek5
(SRP5328)
Other Names NY-REN-55     STK2  
Molecular Weight
(kDa)
180 kDa 50 kDa 55 kDa 90 kDa Not Known
Structural
Datab
1258c aa
Oligomer
445 aa (A)
384 aa (B)
Oligomer
459 aa 841 aa 889 aa
Isoforms Nek1A
Nek1B
Nek2A
Nek2B
Not Known Not Known Not Known
Species Human
Mouse
Fruit fly
Human
Mouse
Xenopus
Fruit fly
Human
Mouse
Human
Mouse
Human
Mouse
Domain
Organization
PK domain
NLS domain
CC domain
PK domain
CC domain
KEN domain
box domain
D-box domain
PK domain
NLS domain
PK domain
NLS domain
PK domain
CC domain
Phosphorylation
Sites
Thr162
other
Not Known Not Known Not Known Not Known
Tissue
Distributiond
Gonad
Nervous system
Testes Small intestine
Testes
Ovary
Testes Not Known
Subcellular
Localization
Cytoplasmic
Centrosomal
Cytoplasmic
Centrosomal
Cytoplasmic Not Known Not Known
Binding Partners/
Associated Proteins
KIF3A
tuberin
α-catulin
cNap1
Hec1
PP1
HMGA2
Nek11
MAD1
Erk2 (M3172)
Not Known Not Known Not Known
Upstream
Activators
Not Known Not Known Not Known Not Known Not Known
Possible
Physiological
Substrates
Not Known cNap1
Hec1
PP1
HMGA2
Nek11
Not Known Not Known Not Known
Activators Not Known Not Known Not Known Not Known Not Known
Inhibitors Not Known Not Known Not Known Not Known Not Known
Selective
Activators
Not Known Not Known Not Known Not Known Not Known
Disease
Relevance
KO causes cystic
kidney disease
Overexpressed in
human breast cancer
Not Known Not Known Not Known

 

 

Family Members Nek6
(N4662, SRP0359)
Nek7
(N4537)
Nek8 Nercc1 Nek10 Nek11
(SRP5051)
Other Names SID6-1512     Nek9
(Nek8a)
   
Molecular Weight
(kDa)
35 kDa 35 kDa 75 kDa 120 kDa Not Known 75 kDa (L)
Structural
Datab
313 aa
Monomer
302 aa
Monomer
703 aa 979 aa 1125 aa 645 aa (L)
470 aa (S)
Isoforms Not Known Not Known Not Known Not Known Not Known Nek11L
Nek11S
Species Human
Mouse
Xenopus
Human
Mouse
Xenopus
Human
Mouse
Zebrafish
Human
Mouse
Xenopus
Human
Mouse
Human
Mouse
Domain
Organization
PK domain PK domain PK domain
RCC1 domain
PK domain
NLS domain
RCC1 domain
CC domain
CC domain
PK domain
CC domain
PK domain
Phosphorylation
Sites
Thr202
Ser206
Other
Thr191
Ser195
Other
Not Known Ser206
Thr210
Other
Not Known Not Known
Tissue
Distributiond
Liver
Placenta
Brain
Intestine
Ovary
Liver
Kidney
Ovary
Testes
Kidney, liver
Testes
Heart
Skeletal muscle
Kidney
Brain
Not Known Not Known
Subcellular
Localization
Not Known Cytoplasmic Cytoplasmic Cytoplasmic Not Known Nuclear
Nucleolar
Binding Partners/
Associated Proteins
Nercc1 Nercc1 Not Known Nek6 (N4662)
Nek7 (N4537)
Ran
Not Known Nek2A
Upstream
Activators
Nercc1 Nercc1 Not Known Not Known Not Known Not Known
Possible
Physiological
Substrates
Cdc16 Cdc16 Not Known Nek6 (N4662)
Nek7 (N4537)
Bicd2
Not Known Not Known
Activators Not Known Not Known Not Known Not Known Not Known Not Known
Inhibitors Not Known Not Known Not Known Not Known Not Known Not Known
Selective
Activators
Not Known Not Known Not Known Not Known Not Known Not Known
Disease
Relevance
Not Known Not Known KO causes cystic
kidney disease
Overexpressed in primary
human breast tumors
Not Known Not Known Not Known

 

Footnotes

a) Nercc1 was also designated as Nek8. As a different NIMA-family member had already been assigned that name, it was later renamed as Nek9. We favor the Nercc1 designation to avoid any confusion.

b) Number of residues corresponds to the human form

c) Originally described as a partial (774 aa) clone from mouse.

d) Only major sites of expression is shown; most of Neks are detected in all tissues at minor levels.

 

References