NEK2

NEK2 Full Name

NIMA (never in mitosis gene a)-related kinase 2

NEK2 Introduction

NEK2 (NIMA-related kinase 2) is a serine/threonine kinase of the NIMA family that operates at the centrosome to prepare the cell for mitosis. The centrosome, the principal microtubule-organizing center of animal cells, is duplicated once per cell cycle, and NEK2 is the kinase that drives the separation of the two duplicated centrosomes at the onset of mitosis by phosphorylating the proteins that tether them together. Phosphorylation of the linker proteins C-Nap1 and rootletin by NEK2 triggers their displacement from the centrosome and the disassembly of the fibers that hold the paired centrosomes close to each other, allowing the two organelles to move apart and establish the poles of the mitotic spindle. Because the assembly of a bipolar spindle depends on this separation, NEK2 activity is essential for accurate chromosome segregation, and its deregulation is a source of the centrosome amplification and chromosomal instability that characterize many cancers. Indeed, NEK2 is overexpressed in a wide range of malignancies, where high levels correlate with poor prognosis, drug resistance, and aneuploidy, and it is regarded as one of the most promising kinases for anticancer drug development. Its expression is tightly cell-cycle regulated, peaking in S and G2 phases, which makes NEK2 an attractive target that is preferentially active in dividing cells.

Figure 1. The structure of NEK2.

Kinase Domain Architecture and Centrosomal Substrates
The NEK2 gene is located on human chromosome 1 and is expressed as two major splice isoforms, NEK2A and NEK2B, which differ in their C-terminal regions and in their regulation during the cell cycle.
The N-terminal kinase domain is followed by a coiled-coil region that mediates dimerization, and dimerization is required for full catalytic activity and for autophosphorylation.
NEK2 localizes to the centrosome throughout the cell cycle, with its levels and activity rising as cells progress through S and G2 phases toward mitosis.
The best-characterized substrates are the centrosomal linker proteins C-Nap1 and rootletin; phosphorylation of these proteins by NEK2 leads to their removal from the centrosome and the dissolution of the linker structure.
NEK2 also phosphorylates additional centrosomal and spindle proteins, including components involved in microtubule nucleation and kinetochore function, broadening its influence over mitotic fidelity.
At the end of mitosis, NEK2A is destroyed through ubiquitin-dependent degradation, ensuring that the kinase does not act inappropriately during the following cell cycle.
The activity of NEK2 is further controlled by phosphorylation and by interactions with regulatory proteins that confine its function to the correct time and place.

Centrosome Separation, Chromosomal Instability, and Cancer
The separation of duplicated centrosomes at the G2/M transition, driven by NEK2-mediated phosphorylation of C-Nap1 and rootletin, is a prerequisite for the formation of the bipolar mitotic spindle.
Failure of this process, or conversely its exaggeration through NEK2 overexpression, perturbs spindle geometry and promotes the formation of extra spindle poles and the missegregation of chromosomes.
NEK2 is overexpressed in a broad spectrum of human cancers, including breast, lung, liver, colorectal, and hematologic malignancies, and high expression is consistently associated with aggressive disease and shorter survival.
Preclinical studies show that silencing or inhibiting NEK2 in tumor cells induces mitotic defects, apoptosis, and reduced tumor growth, and it sensitizes cancer cells to taxane-based chemotherapy.
Because normal cells express low levels of NEK2 and divide less frequently, the kinase has been proposed as a tumor-selective target for antimitotic therapy.
Several small-molecule NEK2 inhibitors have been developed and are being optimized, with the goal of exploiting the dependence of cancer cells on faithful centrosome biology to achieve a therapeutic window over normal tissues.

Alternate Names for NEK2

NEK2; NIMA (never in mitosis gene a)-related kinase 2; serine/threonine-protein kinase Nek2; HsPK 21; NEK2A; NLK1; nimA-like protein kinase 1; nimA-related protein kinase 2; HsPK21;