Roles of kinesin superfamily proteins in colorectal cancer carcinogenesis (Review)
- Authors:
- Published online on: May 5, 2021 https://doi.org/10.3892/or.2021.8072
- Article Number: 121
Abstract
Introduction
Colorectal cancer (CRC) is one of the most frequently occurring carcinomas, ranking third in terms of cancer incidence and second terms of in cancer-related mortality worldwide in 2020 (1). Globally, ~0.9 million CRC-associated deaths are reported annually (2). The incidence of this disease has increased over the past decades in a number of developing countries, possibly owing to changes in lifestyle and aging populations. Tumorigenesis is a complicated biological process regulated by various factors, and requires timely and accurate transport of functional molecules to their targets by motor proteins. Kinesins, a group of motor proteins, act as transporters along microtubules (MTs) (3) and have vital roles in various physiological processes, such as protein sorting and chromosome dynamics. Defects in kinesin function can lead to dysregulated distribution of various proteins and organelles within cells, and have been implicated in numerous diseases, including left-right asymmetry, Alzheimer's disease and amyotrophic lateral sclerosis (4–6). Studies have also revealed a correlation between kinesins and CRC. For example, elevated expression of kinesins positively influences several clinical features, such as lymph node metastasis (7–11) and tumor status (7,9,10,12–14), and is relevant to the overall survival rate of patients with CRC (7,9–13,15). The dysregulation of kinesins affects cell proliferation, tumor formation and metastasis in CRC (7–18). Given the importance of kinesins, the present review aims to illustrate their roles in the prognosis of CRC and the potential underlying regulatory mechanisms involved in CRC carcinogenesis, to provide new targets for the clinical therapy of the disease.
Kinesins
Classification and structure
The kinesin superfamily in humans comprises 45 members classified into 14 families, Kinesin-1 to Kinesin-14, according to their structural differences (19). Kinesin family members (KIFs) vary in shape, but share three distinct domains, the head, stalk and tail, which perform different functions during cargo transportation. The head, which is an orbicular domain, is conserved among different KIF members; this domain binds to the MT and regulates movement through two binding sites: One binds the MT and is characterized by a Rossman fold, while the other binds to ATP (20). There are three elements within the ATP-binding site, Switch-I, Switch-II and the P-loop, which are responsible for the hydrolysis of ATP and contribute to the conformational changes of the MT-binding domain (21). The location of the head correlates with the direction of kinesin movement along the MTs. The head domain of Kinesin-1 to Kinesin-12 family members is found in the NH2-terminal region and moves to the plus ends of MTs; these are called the N-kinesins, whereas Kinesin-14A/B family members are C-kinesins and contain the motor domain at the COOH-terminus and the head for the minus end of the MTs. Kinesin-13 family members are M-kinesins, with the head domain situated in the center of the molecule structure, and these are involved in depolymerizing MTs (9).
In contrast to the conserved head domain, the amino acid sequences in the stalk and tail domains are highly variable (22). Most often, KIFs dimerize with each other to form homo- or heterodimers through the stalk domain, and the dimerization status is determined by the length of this domain. KIFs can also function as monomers. KIFs bind with cargo for its selective transport through the highly variable tail domain and may be accompanied by light chain and/or associated proteins (Fig. 1).
Two mechanisms have been suggested to describe the movements of kinesins: The ‘hand-over-hand’ and ‘inchworm’ models (23). In the ‘hand-over-hand’ model, the front head alternates with the rear one on the MTs to forge ahead, and every step consumes two molecules of ATP. In the ‘inchworm’ model, by contrast, the relative positions of the two heads are maintained, enabling movements of 8 nm for the anterior head (Fig. 2).
Biological activity of kinesins and relevance to diseases
KIFs are responsible for the transport of cellular organelles, functional proteins packed in vesicles and macromolecules such as chromosomes to the required destinations; thus, they are vital for protein sorting and appropriate positioning of various biological molecules (24). Owing to these functions, KIFs are involved in numerous diseases. Kinesin-1 has been reported to interact with key molecules such as adenomatous polyposis coli protein participating in the Wnt signaling pathway (25) and GluN2B, which regulates N-methyl-D-aspartate receptor activity (26). Thus, dysregulated Kinesin-1 potentially causes neurological diseases (27). Selective knockout of KIF5B in pancreatic β cells and adipocytes affects insulin and adipokine secretion, which leads to metabolic disorders (28,29). For organelle transport, KIF5B is found to regulate mitochondrial localization and activity (30), and contributes to pathological hypertrophic responses in cardiomyocytes (31). Moreover, during the cell cycle, kinesins are responsible for the formation of the spindle apparatus and the alignment and detachment of chromosomes (32). Modulations in KIF activity could influence the cell cycle and alter the apoptosis level of cells. The dysregulation of kinesins has also been reported to affect cell multiplication and migration, with effects on the carcinogenesis of various cancer types, including breast and lung cancer (33,34).
Kinesins in CRC
CRC occurs when epithelial cells in the colon and rectum gain the ability for abnormal growth. To date, the expression of 10 KIFs has been reported to be increased in CRC tissue and has been associated with patient prognosis and CRC metastasis (Table I). KIFs interact with intracellular molecules to influence the activity of CRC cells, with effects on proliferation, migration, invasion and the immune reaction (Fig. 3).
Kinesin-3
The Kinesin-3 family is distinguished from conventional kinesins by a peculiar neck region containing a β-sheet and a helix (35), and by the incorporation of a forkhead-associated domain in the tail region. Kinesin-3 motors are essential for organelle transport and cytokinesis, which suggest potential roles of kinesin-3 family members in modulating the cell cycle (36).
KIF14, a member of the Kinesin-3 family, serves as a mitotic kinesin and is encoded by a gene situated on chromosome 1q32.1 (37). In CRC, Wang et al (17) found that elevated KIF14 levels contributed to cell proliferation. Flow cytometry results showed that high KIF14 expression could cause G0/G1 arrest, indicating a role in the modulation of the cell cycle. Additional experiments confirmed that high KIF14 expression increased the phosphorylation of protein kinase B (also known as Akt), thereby advancing the cell cycle to promote tumorigenesis. This study also demonstrated that microRNA such as miR-200c might directly bind to the 1402- to 1409-bp locus of KIF14; thus, miR-200c could negatively regulate KIF14 function to inhibit overgrowth of cells at the post-transcriptional level.
Kinesin-4
Kinesin-4 motors participate in the transportation of organelles and in chromosome dynamics, and are vital to the regulation of cycle phase transitions during mitosis (38). In vertebrates, the Kinesin-4 family has five members (KIF4, KIF7, KIF21, KIF27 and NcKIF21A) and KIF4A plays a significant role in the cell cycle (32,38).
KIF4A forms part of the chromosome condensation and separation machinery (38), and the disordered function of KIF4A affects cell division and chromosome integrity. Hou et al (9) described the marked upregulation of KIF4A and its association with the poor survival rate of patients with CRC. Using Transwell assays, high expression of KIF4A increased the migration of CRC cells and their invasion abilities. Given the role of KIF4A in mitosis, cell cycle analysis was performed. The study showed an accumulation of cells in the G0/G1 phase when KIF4A expression was decreased. Subsequent assays confirmed that KIF4A could accelerate the multiplication of cancer cells by negatively modulating the promoter of the p21 gene (39). p21 is downstream of p53 and serves as a tumor suppressor regulating G0/G1 arrest. Matsumoto et al (8) showed that KIF4A also affected the lymph node metastasis of CRC cells. However, KIF4A was not involved in tumor status, venous invasion or liver metastasis, and did not influence the overall survival rate.
Kinesin-5
Homotetrameric kinesin-5 motors have vital roles in the cell cycle via regulation of spindle formation (40). Thus, Kinesin-5 family members are essential for cell growth and multiplication (41).
Cancer stem cells (CSCs) are involved in the initiation of carcinoma cell growth and tumorigenesis (42). Imai et al (43) detected a significantly upregulated level of KIF11 in gastric cancer (GC) and showed that KIF11 was correlated with the activity of CSCs in GC. A subsequent study used spheroid colony formation assays to measure how KIF11 expression affected the stemness of CRC cells (16). In CRC cells, the KIF11 defect markedly decreased the number and dimension of spheres, indicating an important role of KIF11. However, phenotypic studies indicated that there were no correlations between KIF11 and clinicopathological characteristics.
Kinesin-6
Categorized as an N-type kinesin, Kinesin-6 family members have a conventional structure and are involved in cytokinesis and spindle arrangement (44). This family comprises three proteins, KIF20A, KIF20B and KIF23, two of which have been reported to correlate with CRC progression (12,15).
KIF20A is localized in the Golgi apparatus and is responsible for the converse conveyance of Golgi membranes. Upregulation of KIF20A has been observed in some malignant carcinomas (45). With regard to CRC, Xiong et al (15) demonstrated that KIF20A was upregulated in CRC cells and promoted tumor growth in vivo. From data extracted by the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/) and The Cancer Genome Atlas (TCGA; http://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga), it was found that elevated expression of KIF20A was associated with the poor survival rate of patients with CRC. Furthermore, deficient KIF20A expression could increase the apoptosis of cancer cells after treatment with fluorouracil and oxaliplatin. By contrast, the overexpression of KIF20A via transfection was associated with the downregulation of apoptosis-related proteins, which provided evidence that KIF20A affected the chemoresistance of CRC cells. Notably, this study also showed that increased KIF20A expression contributed to the increased phosphorylation of JAK2 and STAT3. Interference with the JAK2/STAT3 pathway markedly prohibited CRC cell proliferation and reversed the decrease in apoptosis of CRC cells stimulated by the dysregulation of KIF20A. Thus, KIF20A was proposed to promote CRC carcinogenesis by activating the JAK2/STAT3 signaling pathway.
Lin et al (12) found that silencing KIF20B decreased the migration and invasion abilities of cancer cells, and had effects on the expression of the epithelial-mesenchymal transition (EMT)-associated transcription factors Snail and Twist. Subsequent experiments showed that the decrease in glioma-associated oncogene 1 (Gli1) expression was associated with impaired KIF20B expression, while the overexpression of Gli1 could relieve the loss of migration ability of CRC cells resulting from the silencing of KIF20B. Gli1 can activate EMT, thereby promoting cancer metastasis (46). Thus, KIF20B was speculated to stimulate Gli1-mediated EMT. The latter experiments performed by Lin et al (12) also revealed the significance of KIF20B in the formation of cell pseudopod protrusions and actin cytoskeleton dynamics. An evaluation of clinical data found that KIF20B was associated with tumor status and metastasis, and its high expression was correlated with the poor overall survival rate of patients with CRC.
Kinesin-8
Kinesin-8 is indispensable for appropriate allocation of chromosomes in several animal species (47,48). Members of the Kinesin-8 family can modify spindle activity and participate in the segregation of chromosomes (49).
A member of the Kinesin-8 family, KIF18A, serves as an MT depolymerase and plays an important role in chromosome agglutination (50). Nagahara et al (10) showed that increased KIF18A expression notably increased the proliferation, migration and invasion abilities of CRC cells. Zhu et al (51) confirmed that overexpression of KIF18A could accelerate tumor growth in chronic colitis. By contrast, silencing the gene encoding KIF18A increased the apoptosis of tumor cells, which was further confirmed by the observation of the elevated expression of caspase-3 (51). Immunohistochemical assays showed that the phosphorylation level of Akt was significantly decreased in kif18a−/− dysplasia compared with that in the wild-type (51). These data indicated that KIF18A promotes CRC progression and influences apoptosis by regulating Akt signaling.
Kinesin-10
The Kinesin-10 subfamily in humans has a single member termed KIF22, which is also known as Kinesin-like 4 (KNSL4)/Kinesin-like DNA binding protein. KIF22 is a chromokinesin that participates in regulating chromosome dynamics during mitosis (52). KIF22 has two nuclear localization sequences (53) and possesses a helix-hairpin-helix DNA-binding motif feature, which contributes to its activity as a transcription factor and the regulation of gene expression (54). The expression of KIF22 has been reported to be upregulated in CRC, and is correlated with tumor stages, rather than with lymph node metastasis or tumor differentiation (14). In addition, interference with KIF22 expression by short hairpin RNA inhibited cell proliferation in vitro and xenograft tumor growth in in vivo models (14). Since it has been reported that KIF22 modulates the expression of CDC25C, a gene involved in the regulation of CDK1 activity and control of mitosis (55), it is quite possible that KIF22 promotes CRC cell proliferation by regulating CDC25C/CDK1 activity.
Kinesin-11
Characterized by the presence of a divergent catalytic core, Kinesin-11 proteins are distinct from other kinesins and play a role in signal transduction pathways (56).
KIF26B, encoded by a gene situated on the chromosome region lq44 (57), is located downstream of the zinc finger protein Stall1. Wang et al (13) identified a marked upregulation of KIF26B in CRC cells and reported that the expression of KIF26B was associated with tumor size, tumor status and histological differentiation. Survival analyses showed that a high expression level of KIF26B led to low overall survival rate and was a biomarker for a poor prognosis in patients with CRC. Further, defects in KIF26B expression induced a decrease in the expression of cyclin D1 and attenuated CRC cell proliferation.
Kinesin-13
Members of the Kinesin-13 family function as MT depolymerases, participating in the formation and separation of cilia, as well as the regulation of axon development and rehabilitation (58,59). The proteins of this family are M-type kinesins and include KIF2A, KIF2B, KIF2C/MCAK and KIF24 (35).
KIF2A functions as a MT depolymerase. In CRC, Fan et al (7) analyzed the expression of KIF2A in various tissue samples and observed its significant upregulation in cancer tissues compared with that in normal tissues. Furthermore, KIF2A was correlated with TNM stage and tumor status. Specifically, higher expression of KIF2A correlated with later TNM stages and higher levels of lymph node metastasis. However, no correlations were found between KIF2A expression and preoperative carcinoembryonic antigen level, histological type, tumor location or differentiation. Survival analyses also demonstrated the potential value of KIF2A in predicting a poor prognosis in patients with CRC.
MCAK, encoded by a gene on the chromosomal region 1p34.1 (60), catalyzes the disassembly of MTs from both ends by modulation of mitotic kinases (61). Ishikawa et al (11) found that the overexpression of MCAK mRNA expression could predict lymph node metastasis and could be used as an independent predictor of a poor prognosis in patients with CRC. Furthermore, Ritter et al (18) showed that Aurora B, a vital kinase involved in modulating mitosis, could induce the serine-192-mediated phosphorylation of MCAK to influence its catalytic ability and affect tumor metastasis. Interfering with MCAK phosphorylation led to interference with the transition from prometaphase to metaphase and induced abnormalities in chromosome dynamics. Bioinformatics analysis of a variety of single-nucleotide polymorphisms showed that an E403K mutation could also affect MCAK activity and is crucial for CRC progression (62).
NY-CO-58, which is identical to MCAK and KNSL6 (63), is classified as a tumor antigen and interacts with IgG antibodies in patients with CRC (64). Gnjatic et al (65) observed significant upregulation of NY-CO-58/MCAK expression in CRC samples. Notably, NY-CO-58/MCAK also seemed to influence tumor growth, based on the detection of Ki-67 expression, and could stimulate spontaneous T-cell responses consisting mainly of CD4+ T cell-mediated immune reactions. Cytoplasmatic staining indicated that CD4+ T cells stimulated by NY-CO-58/MCAK secreted Th1-type cytokines to evoke an immune response, under the regulation of T regulatory cells.
Summary and perspectives
As the main MT-dependent cellular transporters, kinesins have been studied for decades and have been shown to be involved in a number of diseases. Studies have shown that dysregulated kinesin expression and function could contribute to the tumorigenesis and metastasis of several cancer types, including breast, lung and colon cancer. In CRC, expression levels of KIF14, KIF18A, KIF20A, KIF4A, KIF20B and MCAK have been reported to be associated with tumor progression and prognosis via the regulation of cell survival, the cell cycle, EMT and MT dynamics (Figs. 4 and 5). KIF11, KIF22, KIF26B and KIF2A also contribute to the development of CRC carcinogenesis; however, the underlying mechanisms remain to be identified.
Recent studies have revealed that kinesins regulate CRC cell survival via Akt and JAK2-STAT3 signaling pathways (Fig. 4). Akt serves as a key regulator of signal transduction in several classic pathways. In the PI3K-Akt pathway, PI3K modulates the phosphorylation of Akt via the induction of PIP3, stimulating a cascade able to activate downstream signal molecules such as NF-κB and p53 to control cell survival (66). Additional studies have shown that KIF14 and KIF18A regulate CRC cell proliferation and apoptosis by increased Akt signaling (Fig. 4A). With respect to the JAK2-STAT3 pathway, the activation of the expression of downstream genes such as p53, Bcl-2 and Cyclin D1 is involved in regulating cell growth and apoptosis (67). Xiong et al (15) found that KIF20A modulates the activity of JAK2 and STAT3 to affect CRC tumorigenesis and chemoresistance (Fig. 4B). These studies have provided insight into the KIF-associated signaling pathways that modulate tumor cell proliferation and survival, but further studies are still needed to verify the mechanisms involved.
Dysregulation of cell cycle-related factors can trigger disorders in the cell cycle and cause impairments in cell proliferation (68). p21 is a well-known cyclin-dependent kinases inhibitor (CDKI) that regulates the activities of the CDKs, including cyclin D/CDK4 or CDK6, cyclin E/CDK2, cyclin A/CDK1 (Cdc2) or CDK2, and cyclin B/CDK1, to modulate the cell cycle, serving as a tumor suppressor (69). Hou et al (9) found that the nuclear localization of KIF4A results in its direct binding on the p21 promoter and negative regulation of the expression of p21. Overexpression of KIF4A in CRC has been reported to downregulate p21 expression, which further enhances cell proliferation by promoting cell cycle progression, suggesting that KIF4A-targeted therapy could be effective in inhibiting CRC tumor growth (Fig. 5B).
Epithelial cells undergo EMT to gain migrative and invasive capacity, favoring the metastasis of cancer cells from the primary tumor site to other tissues or organs (Fig. 5A). Tumor metastasis is associated with the aggravation of cancer and a poor prognosis for patients. Lin et al (12) found that KIF20B in pseudopod protrusions promoted cell invasion and metastasis by regulating actin cytoskeleton dynamics, and that knockdown of KIF20B downregulated Gli1 expression and decreased the expression levels of EMT marker proteins. Thus, targeting KIF20B could be a promising treatment approach in cancer therapy (12).
MTs, as components of the cytoskeleton, play crucial roles in cellular transport and spindle dynamics. Furthermore, MCAK acts as a MT depolymerase to regulate the assembly of the mitotic apparatus and disassembly of the sister-chromosome to affect the cell cycle via MT dynamics (70). Overexpression of MCAK has been correlated with several cancer types (71). Ritter et al (18) showed that in CRC, serine 192 was the key site regulating MCAK catalytic ability induced by Aurora B (Fig. 5C). Thus, the regulation of phosphorylation at serine 192 might be a novel way to modulate the activity of MCAK for cancer therapy.
In addition to regulating cell survival, the cell cycle, EMT and MT dynamics, kinesins are also involved in regulating CRC chemoresistance. Fluorouracil and oxaliplatin are anticancer agents that have been used in clinical trials to treat CRC (72,73). Xiong et al (15) found that the overexpression of KIF20A could attenuate the increase in the BAX/BCL-2 ratio induced by fluorouracil and oxaliplatin to protect cancer cells against apoptosis. After knocking down KIF20A, CRC cells underwent increased apoptosis. The contribution of KIF20A to chemoresistance in CRC indicates that kinesins might play a vital role in the clinical therapy of CRC.
Given that a considerable number of kinesins have been found to promote tumorigenesis and growth in CRC, targeting this family of motor proteins seems a promising approach for cancer treatment. Several inhibitors against KIFs have already been tested for their efficacy in the treatment of cancer: Ispinesib, AZD4877, ARRY-520, SB-743921, ARQ 621, LY2523355, MK-0731, EMD534085 and 4SC-205 targeting Eg5; GSK923295 targeting CENPE (KIF10); peptide targeting MPP1 (KIF20B); AZ82 and SR31527 targeting KIFC1; and lidocaine and tetracaine targeting KIF5C (74,75). In CRC, studies have reported novel agents targeting KIF11 (also known as Eg5, a kinesin spindle protein), which can repress tumor progression. Zhang et al (76) identified SRI35566 as a new inhibitor that could interact directly with Eg5. More importantly, SRI35566 could prevent drug resistance, which is common among agents targeting monastrol-binding sites. K858 was shown by Nakai et al (77) to interfere with centrosome separation and cause cell cycle arrest, effectively eliminating cancer cells without damaging MT activity. Considering the crucial roles of KIFs in CRC, more studies are needed to explore the mechanisms by which kinesins influence tumor progression, to provide insight into using kinesins as biomarkers for prediction of CRC progression, and to identify therapeutic targets for efficient treatment of CRC in the future.
Acknowledgements
Not applicable.
Funding
This study was supported, in part, by the National Natural Science Foundation of China (grant nos. 82073264), the Beijing Natural Science Foundation (grant no. 7154234) and the Beijing Hospital Nova Project (grant no. BJ-2016-034). The Shenzhen Peacock project (grant no. KQTD2015033-117210153) also provided support.
Availability of data and materials
Not applicable.
Authors' contributions
DH performed the analysis and wrote the manuscript. HY contributed to the conception of the study. JDH contributed to the conception of the study and revised the manuscript. JPC contributed to the conception of the study. JC contributed to the conception of the study, manuscript preparation and revision. All authors have read and approved the manuscript. Data authentication is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. Feb 4–2021.(Epub ahead of print). doi: 10.3322/caac.21660. View Article : Google Scholar : PubMed/NCBI | |
Dekker E, Tanis PJ, Vleugels JLA, Kasi PM and Wallace MB: Colorectal cancer. Lancet. 394:1467–1480. 2019. View Article : Google Scholar : PubMed/NCBI | |
Vale RD and Milligan RA: The way things move: Looking under the hood of molecular motor proteins. Science. 288:88–95. 2000. View Article : Google Scholar : PubMed/NCBI | |
Nonaka S, Tanaka Y, Okada Y, Takeda S, Harada A, Kanai Y, Kido M and Hirokawa N: Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell. 95:829–837. 1998. View Article : Google Scholar : PubMed/NCBI | |
Goldstein LS: Kinesin molecular motors: Transport pathways, receptors, and human disease. Proc Natl Acad Sci USA. 98:6999–7003. 2001. View Article : Google Scholar : PubMed/NCBI | |
Morel M, Héraud C, Nicaise C, Suain V and Brion JP: Levels of kinesin light chain and dynein intermediate chain are reduced in the frontal cortex in Alzheimer's disease: Implications for axoplasmic transport. Acta neuropathol. 123:71–84. 2012. View Article : Google Scholar : PubMed/NCBI | |
Fan X, Wang X, Zhu H, Wang W, Zhang S and Wang Z: KIF2A overexpression and its association with clinicopathologic characteristics and unfavorable prognosis in colorectal cancer. Tumour Biol. 36:8895–8902. 2015. View Article : Google Scholar : PubMed/NCBI | |
Matsumoto Y, Saito M, Saito K, Kanke Y, Watanabe Y, Onozawa H, Hayase S, Sakamoto W, Ishigame T, Momma T, et al: Enhanced expression of KIF4A in colorectal cancer is associated with lymph node metastasis. Oncol Lett. 15:2188–2194. 2018.PubMed/NCBI | |
Hou PF, Jiang T, Chen F, Shi PC, Li HQ, Bai J and Song J: KIF4A facilitates cell proliferation via induction of p21-mediated cell cycle progression and promotes metastasis in colorectal cancer. Cell Death Dis. 9:4772018. View Article : Google Scholar : PubMed/NCBI | |
Nagahara M, Nishida N, Iwatsuki M, Ishimaru S, Mimori K, Tanaka F, Nakagawa T, Sato T, Sugihara K, Hoon DS and Mori M: Kinesin 18A expression: Clinical relevance to colorectal cancer progression. Int J Cancer. 129:2543–2552. 2011. View Article : Google Scholar : PubMed/NCBI | |
Ishikawa K, Kamohara Y, Tanaka F, Haraguchi N, Mimori K, Inoue H and Mori M: Mitotic centromere-associated kinesin is a novel marker for prognosis and lymph node metastasis in colorectal cancer. Br J Cancer. 98:1824–1829. 2008. View Article : Google Scholar : PubMed/NCBI | |
Lin WF, Lin XL, Fu SW, Yang L, Tang CT, Gao YJ, Chen HY and Ge ZZ: Pseudopod-associated protein KIF20B promotes Gli1-induced epithelial-mesenchymal transition modulated by pseudopodial actin dynamic in human colorectal cancer. Mol Carcinog. 57:911–925. 2018. View Article : Google Scholar : PubMed/NCBI | |
Wang J, Cui F, Wang X, Xue Y, Chen J, Yu Y, Lu H, Zhang M, Tang H and Peng Z: Elevated kinesin family member 26B is a prognostic biomarker and a potential therapeutic target for colorectal cancer. J Exp Clin Cancer Res. 34:132015. View Article : Google Scholar : PubMed/NCBI | |
Li B, Zhu FC, Yu SX, Liu SJ and Li BY: Suppression of KIF22 inhibits cell proliferation and xenograft tumor growth in colon cancer. Cancer Biother Radiopharm. 35:50–57. 2020. View Article : Google Scholar : PubMed/NCBI | |
Xiong M, Zhuang K, Luo Y, Lai Q, Luo X, Fang Y, Zhang Y, Li A and Liu S: KIF20A promotes cellular malignant behavior and enhances resistance to chemotherapy in colorectal cancer through regulation of the JAK/STAT3 signaling pathway. Aging (Albany NY). 11:11905–11921. 2019. View Article : Google Scholar : PubMed/NCBI | |
Imai T, Oue N, Sentani K, Sakamoto N, Uraoka N, Egi H, Hinoi T, Ohdan H, Yoshida K and Yasui W: KIF11 is required for spheroid formation by oesophageal and colorectal cancer cells. Anticancer Res. 37:47–55. 2017. View Article : Google Scholar : PubMed/NCBI | |
Wang ZZ, Yang J, Jiang BH, Di JB, Gao P, Peng L and Su XQ: KIF14 promotes cell proliferation via activation of Akt and is directly targeted by miR-200c in colorectal cancer. Int J Oncol. 53:1939–1952. 2018.PubMed/NCBI | |
Ritter A, Sanhaji M, Friemel A, Roth S, Rolle U, Louwen F and Yuan J: Functional analysis of phosphorylation of the mitotic centromere-associated kinesin by Aurora B kinase in human tumor cells. Cell cycle. 14:3755–3767. 2015. View Article : Google Scholar : PubMed/NCBI | |
Lawrence CJ, Dawe RK, Christie KR, Cleveland DW, Dawson SC, Endow SA, Goldstein LS, Goodson HV, Hirokawa N, Howard J, et al: A standardized kinesin nomenclature. J Cell Biol. 167:19–22. 2004. View Article : Google Scholar : PubMed/NCBI | |
Hirokawa N, Noda Y, Tanaka Y and Niwa S: Kinesin superfamily motor proteins and intracellular transport. Nat Rev Mol Cell Biol. 10:682–696. 2009. View Article : Google Scholar : PubMed/NCBI | |
Woehlke G and Schliwa M: Walking on two heads: The many talents of kinesin. Nat Rev Mol Cell Biol. 1:50–58. 2000. View Article : Google Scholar : PubMed/NCBI | |
Sack S, Kull FJ and Mandelkow E: Motor proteins of the kinesin family. Structures, variations, and nucleotide binding sites. Eur J Biochem. 262:1–11. 1999. View Article : Google Scholar : PubMed/NCBI | |
Hua W, Chung J and Gelles J: Distinguishing inchworm and hand-over-hand processive kinesin movement by neck rotation measurements. Science. 295:844–848. 2002. View Article : Google Scholar : PubMed/NCBI | |
Vale RD: The molecular motor toolbox for intracellular transport. Cell. 112:467–480. 2003. View Article : Google Scholar : PubMed/NCBI | |
Ruane PT, Gumy LF, Bola B, Anderson B, Wozniak MJ, Hoogenraad CC and Allan VJ: Tumour suppressor adenomatous polyposis Coli (APC) localisation is regulated by both Kinesin-1 and Kinesin-2. Sci Rep. 6:274562016. View Article : Google Scholar : PubMed/NCBI | |
Lin R, Duan Z, Sun H, Fung ML, Chen H, Wang J, Lau CF, Yang D, Liu Y, Ni Y, et al: Kinesin-1 regulates extrasynaptic targeting of NMDARs and neuronal vulnerability toward excitotoxicity. iScience. 13:82–97. 2019. View Article : Google Scholar : PubMed/NCBI | |
Hirokawa N, Niwa S and Tanaka Y: Molecular motors in neurons: Transport mechanisms and roles in brain function, development, and disease. Neuron. 68:610–638. 2010. View Article : Google Scholar : PubMed/NCBI | |
Cui J, Wang Z, Cheng Q, Lin R, Zhang XM, Leung PS, Copeland NG, Jenkins NA, Yao KM and Huang JD: Targeted inactivation of kinesin-1 in pancreatic β-cells in vivo leads to insulin secretory deficiency. Diabetes. 60:320–330. 2011. View Article : Google Scholar : PubMed/NCBI | |
Cui J, Pang J, Lin YJ, Gong H, Wang ZH, Li YX, Li J, Wang Z, Jiang P, Dai DP, et al: Adipose-specific deletion of Kif5b exacerbates obesity and insulin resistance in a mouse model of diet-induced obesity. FASEB J. 31:2533–2547. 2017. View Article : Google Scholar : PubMed/NCBI | |
Tanaka Y, Kanai Y, Okada Y, Nonaka S, Takeda S, Harada A and Hirokawa N: Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria. Cell. 93:1147–1158. 1998. View Article : Google Scholar : PubMed/NCBI | |
Tigchelaar W, de Jong AM, Bloks VW, van Gilst WH, de Boer RA and Silljé HH: Hypertrophy induced KIF5B controls mitochondrial localization and function in neonatal rat cardiomyocytes. J Mol Cell Cardiol. 97:70–81. 2016. View Article : Google Scholar : PubMed/NCBI | |
Zhu C, Zhao J, Bibikova M, Leverson JD, Bossy-Wetzel E, Fan JB, Abraham RT and Jiang W: Functional analysis of human microtubule-based motor proteins, the kinesins and dyneins, in mitosis/cytokinesis using RNA interference. Mol Biol Cell. 16:3187–3199. 2005. View Article : Google Scholar : PubMed/NCBI | |
Lukong KE and Richard S: Breast tumor kinase BRK requires kinesin-2 subunit KAP3A in modulation of cell migration. Cell Signal. 20:432–442. 2008. View Article : Google Scholar : PubMed/NCBI | |
Corson TW, Zhu CQ, Lau SK, Shepherd FA, Tsao MS and Gallie BL: KIF14 messenger RNA expression is independently prognostic for outcome in lung cancer. Clin Cancer Res. 13:3229–3234. 2007. View Article : Google Scholar : PubMed/NCBI | |
Miki H, Okada Y and Hirokawa N: Analysis of the kinesin superfamily: Insights into structure and function. Trends Cell Biol. 15:467–476. 2005. View Article : Google Scholar : PubMed/NCBI | |
Siddiqui N and Straube A: Intracellular cargo transport by Kinesin-3 motors. Biochemistry (Mosc). 82:803–815. 2017. View Article : Google Scholar : PubMed/NCBI | |
Corson TW, Huang A, Tsao MS and Gallie BL: KIF14 is a candidate oncogene in the 1q minimal region of genomic gain in multiple cancers. Oncogene. 24:4741–4753. 2005. View Article : Google Scholar : PubMed/NCBI | |
Mazumdar M, Sundareshan S and Misteli T: Human chromokinesin KIF4A functions in chromosome condensation and segregation. J Cell Biol. 166:613–620. 2004. View Article : Google Scholar : PubMed/NCBI | |
Karimian A, Ahmadi Y and Yousefi B: Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair (Amst). 42:63–71. 2016. View Article : Google Scholar : PubMed/NCBI | |
Waitzman JS and Rice SE: Mechanism and regulation of kinesin-5, an essential motor for the mitotic spindle. Biol Cell. 106:1–12. 2014. View Article : Google Scholar : PubMed/NCBI | |
Jiang M, Zhuang H, Xia R, Gan L, Wu Y, Ma J, Sun Y and Zhuang Z: KIF11 is required for proliferation and self-renewal of docetaxel resistant triple negative breast cancer cells. Oncotarget. 8:92106–92118. 2017. View Article : Google Scholar : PubMed/NCBI | |
Takaishi S, Okumura T and Wang TC: Gastric cancer stem cells. J Clin Oncol. 26:2876–2882. 2008. View Article : Google Scholar : PubMed/NCBI | |
Imai T, Oue N, Nishioka M, Mukai S, Oshima T, Sakamoto N, Sentani K, Matsusaki K, Yoshida K and Yasui W: Overexpression of KIF11 in gastric cancer with intestinal mucin phenotype. Pathobiology. 84:16–24. 2017. View Article : Google Scholar : PubMed/NCBI | |
Cesario JM, Jang JK, Redding B, Shah N, Rahman T and McKim KS: Kinesin 6 family member Subito participates in mitotic spindle assembly and interacts with mitotic regulators. J Cell Sci. 119:4770–4780. 2006. View Article : Google Scholar : PubMed/NCBI | |
Imai K, Hirata S, Irie A, Senju S, Ikuta Y, Yokomine K, Harao M, Inoue M, Tomita Y, Tsunoda T, et al: Identification of HLA-A2-restricted CTL epitopes of a novel tumour-associated antigen, KIF20A, overexpressed in pancreatic cancer. Br J Cancer. 104:300–307. 2011. View Article : Google Scholar : PubMed/NCBI | |
Zhang C, Wang Y, Feng Y, Zhang Y, Ji B, Wang S and Sun Y, Zhu C, Zhang D and Sun Y: Gli1 promotes colorectal cancer metastasis in a Foxm1-dependent manner by activating EMT and PI3K-AKT signaling. Oncotarget. 7:86134–86147. 2016. View Article : Google Scholar : PubMed/NCBI | |
Pinder C, Matsuo Y, Maurer SP and Toda T: Kinesin-8 and Dis1/TOG collaborate to limit spindle elongation from prophase to anaphase A for proper chromosome segregation in fission yeast. J Cell Sci. 132:jcs2323062019. View Article : Google Scholar : PubMed/NCBI | |
Edzuka T and Goshima G: Drosophila kinesin-8 stabilizes the kinetochore-microtubule interaction. J Cell Biol. 218:474–488. 2019. View Article : Google Scholar : PubMed/NCBI | |
Gardner MK, Odde DJ and Bloom K: Kinesin-8 molecular motors: Putting the brakes on chromosome oscillations. Trends Cell Biol. 18:307–310. 2008. View Article : Google Scholar : PubMed/NCBI | |
Mayr MI, Hümmer S, Bormann J, Grüner T, Adio S, Woehlke G and Mayer TU: The human kinesin Kif18A is a motile microtubule depolymerase essential for chromosome congression. Curr Biol. 17:488–498. 2007. View Article : Google Scholar : PubMed/NCBI | |
Zhu H, Xu W, Zhang H, Liu J, Xu H, Lu S, Dang S, Kuang Y, Jin X and Wang Z: Targeted deletion of Kif18a protects from colitis-associated colorectal (CAC) tumors in mice through impairing Akt phosphorylation. Biochem Biophys Res Commun. 438:97–102. 2013. View Article : Google Scholar : PubMed/NCBI | |
Levesque AA and Compton DA: The chromokinesin Kid is necessary for chromosome arm orientation and oscillation, but not congression, on mitotic spindles. J Cell Biol. 154:1135–1146. 2001. View Article : Google Scholar : PubMed/NCBI | |
Tahara K, Takagi M, Ohsugi M, Sone T, Nishiumi F, Maeshima K, Horiuchi Y, Tokai-Nishizumi N, Imamoto F, Yamamoto T, et al: Importin-beta and the small guanosine triphosphatase Ran mediate chromosome loading of the human chromokinesin Kid. J Cell Biol. 180:493–506. 2008. View Article : Google Scholar : PubMed/NCBI | |
Tokai N, Fujimoto-Nishiyama A, Toyoshima Y, Yonemura S, Tsukita S, Inoue J and Yamamota T: Kid, a novel kinesin-like DNA binding protein, is localized to chromosomes and the mitotic spindle. EMBO J. 15:457–467. 1996. View Article : Google Scholar : PubMed/NCBI | |
Yu Y, Wang XY, Sun L, Wang YL, Wan YF, Li XQ and Feng YM: Inhibition of KIF22 suppresses cancer cell proliferation by delaying mitotic exit through upregulating CDC25C expression. Carcinogenesis. 35:1416–1425. 2014. View Article : Google Scholar : PubMed/NCBI | |
Zhou R, Niwa S, Homma N, Takei Y and Hirokawa N: KIF26A is an unconventional kinesin and regulates GDNF-Ret signaling in enteric neuronal development. Cell. 139:802–813. 2009. View Article : Google Scholar : PubMed/NCBI | |
Orellana C, Roselló M, Monfort S, Oltra S, Quiroga R, Ferrer I and Martínez F: Corpus callosum abnormalities and the controversy about the candidate genes located in 1q44. Cytogenet Genome Res. 127:5–8. 2009. View Article : Google Scholar : PubMed/NCBI | |
Miyamoto T, Hosoba K, Ochiai H, Royba E, Izumi H, Sakuma T, Yamamoto T, Dynlacht BD and Matsuura S: The Microtubule-Depolymerizing activity of a mitotic kinesin protein KIF2A drives primary cilia disassembly coupled with cell proliferation. Cell Rep. 10:664–673. 2015. View Article : Google Scholar : PubMed/NCBI | |
Vasudevan KK, Jiang YY, Lechtreck KF, Kushida Y, Alford LM, Sale WS, Hennessey T and Gaertig J: Kinesin-13 regulates the quantity and quality of tubulin inside cilia. Mol Biol Cell. 26:478–494. 2015. View Article : Google Scholar : PubMed/NCBI | |
Wordeman L and Mitchison TJ: Identification and partial characterization of mitotic centromere-associated kinesin, a kinesin-related protein that associates with centromeres during mitosis. J Cell Biol. 128:95–104. 1995. View Article : Google Scholar : PubMed/NCBI | |
Helenius J, Brouhard G, Kalaidzidis Y, Diez S and Howard J: The depolymerizing kinesin MCAK uses lattice diffusion to rapidly target microtubule ends. Nature. 441:115–119. 2006. View Article : Google Scholar : PubMed/NCBI | |
Kumar A, Rajendran V, Sethumadhavan R and Purohit R: Evidence of colorectal cancer-associated mutation in MCAK: A computational report. Cell Biochem Biophys. 67:837–851. 2013. View Article : Google Scholar : PubMed/NCBI | |
Aoki S, Ohta K, Yamazaki T, Sugawara F and Sakaguchi K: Mammalian mitotic centromere-associated kinesin (MCAK): A new molecular target of sulfoquinovosylacylglycerols novel antitumor and immunosuppressive agents. FEBS J. 272:2132–2140. 2005. View Article : Google Scholar : PubMed/NCBI | |
Scanlan MJ, Welt S, Gordon CM, Chen YT, Gure AO, Stockert E, Jungbluth AA, Ritter G, Jäger D, Jäger E, et al: Cancer-related serological recognition of human colon cancer: Identification of potential diagnostic and immunotherapeutic targets. Cancer Res. 62:4041–4047. 2002.PubMed/NCBI | |
Gnjatic S, Cao Y, Reichelt U, Yekebas EF, Nölker C, Marx AH, Erbersdobler A, Nishikawa H, Hildebrandt Y, Bartels K, et al: NY-CO-58/KIF2C is overexpressed in a variety of solid tumors and induces frequent T cell responses in patients with colorectal cancer. Int J Cancer. 127:381–393. 2010.PubMed/NCBI | |
Osaki M, Oshimura M and Ito H: PI3K-Akt pathway: Its functions and alterations in human cancer. Apoptosis. 9:667–676. 2004. View Article : Google Scholar : PubMed/NCBI | |
Carpenter RL and Lo HW: STAT3 target genes relevant to human cancers. Cancers (Basel). 6:897–925. 2014. View Article : Google Scholar : PubMed/NCBI | |
Kramer HB, Lai CF, Patel H, Periyasamy M, Lin ML, Feller SM, Fuller-Pace FV, Meek DW, Ali S and Buluwela L: LRH-1 drives colon cancer cell growth by repressing the expression of the CDKN1A gene in a p53-dependent manner. Nucleic Acids Res. 44:582–594. 2016. View Article : Google Scholar : PubMed/NCBI | |
Lim S and Kaldis P: Cdks, cyclins and CKIs: Roles beyond cell cycle regulation. Development. 140:3079–3093. 2013. View Article : Google Scholar : PubMed/NCBI | |
Braun A, Dang K, Buslig F, Baird MA, Davidson MW, Waterman CM and Myers KA: Rac1 and Aurora A regulate MCAK to polarize microtubule growth in migrating endothelial cells. J Cell Biol. 206:97–112. 2014. View Article : Google Scholar : PubMed/NCBI | |
Shimo A, Tanikawa C, Nishidate T, Lin ML, Matsuda K, Park JH, Ueki T, Ohta T, Hirata K, Fukuda M, et al: Involvement of kinesin family member 2C/mitotic centromere-associated kinesin overexpression in mammary carcinogenesis. Cancer Sci. 99:62–70. 2008.PubMed/NCBI | |
Yamada Y, Takahari D, Matsumoto H, Baba H, Nakamura M, Yoshida K, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, et al: Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): An open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 14:1278–1286. 2013. View Article : Google Scholar : PubMed/NCBI | |
Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, et al: Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME study. J Clin Oncol. 28:4697–4705. 2010. View Article : Google Scholar : PubMed/NCBI | |
Lucanus AJ and Yip GW: Kinesin superfamily: Roles in breast cancer, patient prognosis and therapeutics. Oncogene. 37:833–838. 2018. View Article : Google Scholar : PubMed/NCBI | |
Rath O and Kozielski F: Kinesins and cancer. Nat Rev Cancer. 12:527–539. 2012. View Article : Google Scholar : PubMed/NCBI | |
Zhang W, Zhai L, Lu W, Boohaker RJ, Padmalayam I and Li Y: Discovery of novel allosteric Eg5 Inhibitors through structure-based virtual screening. Chem Biol Drug Des. 88:178–187. 2016. View Article : Google Scholar : PubMed/NCBI | |
Nakai R, Iida S, Takahashi T, Tsujita T, Okamoto S, Takada C, Akasaka K, Ichikawa S, Ishida H, Kusaka H, et al: K858, a novel inhibitor of mitotic kinesin Eg5 and antitumor agent, induces cell death in cancer cells. Cancer Res. 69:3901–3909. 2009. View Article : Google Scholar : PubMed/NCBI | |
Zong H, Carnes SK, Moe C, Walczak CE and Ems-McClung SC: The far C-terminus of MCAK regulates its conformation and spindle pole focusing. Mol Biol Cell. 27:1451–1464. 2016. View Article : Google Scholar : PubMed/NCBI |