View source for Kinase Subfamily NEK6

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[[kinase classification|Kinase Classification]]: [[Kinase_Group_Other|Group Other]]: [[Kinase_Family_NEK|Family NEK]]: [[Kinase_Subfamily_NEK6|Subfamily NEK6]]

NEK6 regulates spindle formation during mitosis and modulates cytokinesis and endocytosis, and is regulated by [[Kinase_Subfamily_NEK9|NEK9]].

====Evolution====
NEK6 is found in most eukaryotes, but lost from some insects, including Drosophila, from most fungi, and from higher plants. It has two members in vertebrates, NEK6 and NEK7.

====Domain Structure====
NEK6 consists of a kinase domain, with a short, weakly conserved and unstructured N-terminal extension <cite>Meirelles</cite>.

====Functions====

====Mitosis and Cytokineses====
Mammalian NEK6 and NEK7 have several shared functions. Both are activated in mitosis and required for cell cycle <cite>ORegan, Yin</cite>. Both are activated by the [[Kinase_Subfamily_NEK9|NEK9]] kinase, which is activated in mitosis, and binds NEK6 via the NEK9 C-terminal tail, and is capable of phosphorylating both kinases on the activation loop  <cite>Belham</cite>. Mutants typically arrest in prophase-metaphase

Several phosphorylation targets of NEK6/7 in spindle formation have been described: NEK6 and NEK7 both phosphorylate the microtubule regulator EML4, counteracting its function to stabilize microtubles <cite>Adib</cite>. NEK6 binds and phosphorylates the kinesin KIF11/Eg5 during mitosis, and the phosphoryaltion is required for bipolar spindle formation <cite> Rapley </cite>. NEK6 also phosphorylates KIF20A/MKLP2 to localize it to the anaphase central spindle, while NEK7 regulates KIF14, to recruit CRIK/Citron kinase to the anaphase midzone <cite>Cullati</cite>. NEK6 and NEK7 both phosphorylate the nucleoporin NUP98 in vitro and are thought to lead to nuclear envelope permeability in mitosis <cite>Laurell</cite>.

====Endocytosis====
The C. elegans member, nekl-3/F19H6.1 controls clathrin-mediated endocytosis, along with nekl-2 (NEK8 subfamily)  <cite>Joseph, Yochem</cite> . Human NEKs were able to rescue the worm mutants. The two NEKs were localized by specific ankryin repeat proteins, MLT2-4 <cite>Lazetic</cite>. MLT-3 interacts specifically with nekl-3, and it's mammalian homolog, Anks6, specifically interacts with Nek7, and is implicated in cilium biology. The spindle and endocytosis functions may be linked, since clathrin is also involved in mitotic spindle stabilization and centrosome function <cite>Royle</cite>. RNAi library screening of human kinases for endocytosis defects also showed NEK6 and NEK7 to be required for clathrin-mediated endocytosis, with weaker effects from NEK8 or NEK9 knockdown <cite>Joseph</cite>.

====NEK6 and Cancer, DNA damage and senesence====
NEK6 is overexpressed in several cancers, and tissue culture and xenograft studies show that drives cancer cell survival and anchorage-independent growth <cite>Nassirpour</cite>. NEK6 was identified in a screen for mediators of castration resistance in prostate cancer <cite>Choudry</cite>, which also identified FOXL2 as a novel substrate. NEK6 is reported to bind SMAD4 and block its nuclear localization and block TGFb signaling <cite>Zuo</cite>, to bind and phosphorylate STAT3 on S727, activating it for cell transformation <cite>Jeon</cite>, and to bind the cancer-related prolyl hydroxylase, Pin1 <cite>Chen</cite>.

NEK6 has been reported to block p53-induced senesence, and overexpression could interfere with senesence-driving cancer drugs like camptothecin and doxorubicin <cite>Jee</cite>. NEK6 is phosphorylated by UV and IR radiation, possibly through Chk1 and Chk2, and radiation blocks its mitotic activation <cite>Lee</cite>. Human NEK6 is also reported to phosphorylate the telomerase regulator TPP1 on S255 during mitosis <cite>Hirai</cite>.

====References====
<biblio>
#Yin pmid=14563848
#Joseph pmid=32069276
#Yochem pmid=25523392
#Lazetic pmid=27799278
#Ramachandran pmid=26188091
#ORegan pmid=19414596
#Belham pmid=12840024
#Meirelles pmid=21320329
#Rapley pmid=19001501
#Adib pmid=31409757
#Hirai pmid=27396482
#Cullati pmid=28630147
#Royle pmid=22294613
#Laurell pmid=21335236
#Pelkmans pmid=15889048
#Jee pmid=21539811
#Lee pmid=18728393
#Nassirpour pmid=20407017
#Choudry pmid=27899381
#Zuo pmid=25523445
#Jeon pmid=20595392
#Chen pmid=16476580
</biblio>