Disease relevance of KIF11

• Eg5 expression is closely correlated with the response of advanced non-small cell lung cancer to antimitotic agents combined with platinum chemotherapy [1].
• Genomic amplification in retinoblastoma narrowed to 0.6 megabase on chromosome 6p containing a kinesin-like gene, RBKIN [2].
• Inhibition of the mitotic kinesin Eg5 up-regulates Hsp70 through the phosphatidylinositol 3-kinase/Akt pathway in multiple myeloma cells [3].
• A new study has found that polymorphisms in the host gene kif1C, which encodes a kinesin-like motor protein, determine whether mouse macrophages are resistant or sensitive to anthrax lethal toxin [4].
• Furthermore, HR22C16 along with its analogs, inhibit cell survival in both Taxol-sensitive and -resistant ovarian cancer cells with at least 15-fold greater efficacy than monastrol, the first generation Eg5 inhibitor [5].

Psychiatry related information on KIF11

• Thus, through microtubule cross-linking and oppositely oriented motor activity, HSET and Eg5 participate in spindle assembly and promote spindle bipolarity, although the activity of HSET is not essential for spindle assembly and function in cultured cells because of centrosomes [6].

High impact information on KIF11

• Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo [7].
• Here we identify CENP-E as a kinesin-like motor protein (M(r) 312,000) that accumulates in the G2 phase of the cell cycle [8].
• Single molecules of kinesin, a long-distance cargo transporter, are highly processive, binding the microtubule and taking 100 or more sequential steps at velocities of up to 700nm/s before dissociating, whereas Eg5, a motor active in mitotic spindle assembly, is also processive, but takes fewer steps at a slower rate [9].
• This enzyme also functions in cytokinesis apparently by interacting with a critical GTPase and a kinesin-like protein [10].
• Several kinesin-like motor proteins have recently been found associated with chromosome arms [11].

Chemical compound and disease context of KIF11

• A nuclear kinesin-like protein interacts with and stimulates the activity of the leucine-rich nuclear export signal of the human immunodeficiency virus type 1 rev protein [12].
• Regulation and targeting of Eg5, a mitotic motor protein in blast crisis CML: overcoming imatinib resistance [13].
• Our findings suggest that Eg5 is downstream of and regulated by Bcr-Abl tyrosine kinase in Philadelphia chromosome positive cells [13].

Biological context of KIF11

• Within the first region of deletion at 10q23.33-10q24.1, around microsatellite marker D10S185 (2.77 Mb), 23 genes were identified, including three (KIF11, HHEX, and HELLS) with functions that, if dysregulated, could be critical in MF and SS [14].
• Nine polymorphisms in IDE and four polymorphisms in KIF11 situated in conserved regions or near coding exons were subsequently genotyped in a set of AD cases and controls [15].
• Monastrol is a small, cell-permeable molecule that arrests cells in mitosis by specifically inhibiting Eg5, a member of the Kinesin-5 family [16].
• We propose that S-monastrol binding to Eg5 induces a stable conformational change in the motor domain that favors ATP re-synthesis after ATP hydrolysis [16].
• Eg5 is a kinesin implicated in the formation of the bipolar spindle and its movement prior to and during anaphase [17].

Anatomical context of KIF11

• Immunocytochemical analysis revealed that many oocytes displayed aberrant expression of NuMA and EG5, had disrupted meiotic spindles and tetrapolar spindles [18].
• Monastrol promotes a dramatic decrease in the observed rate of Eg5 association with microtubules, and ADP release is slowed without trapping the Mt.Eg5.ADP intermediate [16].
• Eg5 is a slow, plus-end-directed microtubule-based motor of the BimC kinesin family that is essential for bipolar spindle formation during eukaryotic cell division [19].
• These antibodies were found to recognize kinesin in rat brain extracts as well as kinesin-like polypeptides in extracts of human neutrophils [20].
• Recent studies demonstrate that kinesin, kinesin-like proteins and kinesin-associated proteins can be phosphorylated, and suggest that changes in their phosphorylation state may modulate kinesin's ability to interact with either microtubules or organelles [21].

Associations of KIF11 with chemical compounds

• A pathway of structural changes produced by monastrol binding to Eg5 [22].
• PATIENTS AND METHODS: Eg5 expression was investigated immunohistochemically in 122 formalin-fixed tumor samples from untreated stage IIIB or IV NSCLC patients [1].
• Among nine different human kinesins tested, S-trityl-L-cysteine is specific for Eg5 [23].
• In conclusion, our data suggest an involvement of tyrosine phosphorylation in the regulation of the Golgi to ER membrane flow and describe a new kinesin-like motor protein responsible for this transport [24].
• Structure of Human Eg5 in Complex with a New Monastrol-based Inhibitor Bound in the R Configuration [25].

Physical interactions of KIF11

• This protein is BRCA2-associated factor 35 (BRAF35) containing a non-specific DNA binding high-mobility-group domain and a kinesin-like coiled-coil domain [26].

Enzymatic interactions of KIF11

• Whereas CDK1 phosphorylates nearly all Eg5 at Thr926 during mitosis, Nek6 phosphorylates approximately 3% of Eg5, primarily at the spindle poles [27].

Regulatory relationships of KIF11

• Instead, Parkin represses Eg5 gene transcription by blocking c-Jun binding to the activator protein 1 site present in the Eg5 promoter [28].

Other interactions of KIF11

• Two oocytes expressed EG5 messenger RNA (mRNA), and HSET and NuMA were not detectable [18].
• MSA-like sequences are also found in the promoters of G2/M-specific genes encoding kinesin-like proteins, suggesting that a defined set of G2/M-specific genes are co-regulated by a common MSA-mediated mechanism in plants [29].
• The response to chemotherapy was compared in relation to Eg5 and cyclin B1 expression and in relation to clinicopathological factors [1].
• Presence of the mutant Cu/Zn SOD was confirmed to lead to a decrease in expression of KIF3B, a kinesin-like protein, which forms part of the KIF3 molecular motor. c-Fes, thought to be involved in intracellular vesicle transport was also decreased, further implicating the involvement of vesicular trafficking as a mode of action for mutant Cu/Zn SOD [30].
• Characterization of KIF1C, a new kinesin-like protein involved in vesicle transport from the Golgi apparatus to the endoplasmic reticulum [24].

Analytical, diagnostic and therapeutic context of KIF11

• We have analyzed two human Eg5/KSP motors, Eg5-367 and Eg5-437, and both are monomeric based on results from sedimentation velocity and sedimentation equilibrium centrifugation as well as analytical gel filtration [19].
• CONCLUSIONS: Eg5 expression can predict a response to antimitotic agents combined with platinum chemotherapy among patients with advanced NSCLC [1].
• Roles of kinesin and kinesin-like proteins in sea urchin embryonic cell division: evaluation using antibody microinjection [31].
• We interpret these data as revealing the existence of a static spindle matrix that promotes Eg5 targeting to spindles, and transient immobilization of Eg5 within spindles [32].
• Using affinity chromatography we first show that the compound HR22C16 is an Eg5 inhibitor and does not interact with other microtubule motor proteins tested [5].

References