Identification of a link between the tumour suppressor APC and the kinesin superfamily

Jimbo, Takahiro; Kawasaki, Yuki; Koyama, Ryo; Sato, Ryo; Takada, Shinji; Haraguchi, Keiko; Akiyama, Tetsu

doi:10.1038/ncb779

Cited by 285 publications

(263 citation statements)

References 19 publications

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“…There is also recent functional evidence that dynein mediates the trafficking of MT-bound p53 toward the nucleus upon activation (4) and that hsp90-binding immunophilins link p53 to dynein during this transport (54). More surprisingly, interactions may also take place that involve kinesins as the MLK2 kinase (5) or the tumor suppressor APC were shown to interact with the kinesin-like KIF3 (55). Cubitus interruptus is bound to the kinesin-related protein Costal 2 in the Hedgehog signaling pathway (56,57), and JIP scaffolding proteins for the JNK signaling pathway were found to bind conventional kinesin (58).…”

Section: Figmentioning

confidence: 99%

STAT5B-mediated Growth Hormone Signaling Is Organized by Highly Dynamic Microtubules in Hepatic Cells

Phung-Koskas

Pilon

Poüs

et al. 2005

Journal of Biological Chemistry

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In the last decade, the notion that microtubules are critical to the spatial organization of signal transduction and contribute to the transmission of signals to downstream targets has been proposed. Because the STAT5B transduction and transcription factor is the major STAT protein activated by growth hormone stimulation in hepatocytes and is a crossroads between many signaling pathways, we studied the involvement of microtubules in STAT5B-mediated growth hormone signaling pathway in the highly differentiated and polarized WIF-B hepatic cell line. We showed that depolymerization of the microtubule network impaired STAT5B translocation to the nucleus upon growth hormone treatment. A significant amount of STAT5B binds to microtubules, while STAT5A and STAT3 are exclusively compartmentalized in the cytosol. Moreover, taxol-induced stabilization of microtubules released STAT5B from its binding, and we show that STAT5B binds specifically to the highly dynamic microtubules and is absent of the stable microtubule subpopulation. The specific involvement of dynamic microtubule subpopulation in growth hormone signaling pathway was confirmed by the inhibition of growth hormone-induced STAT5B nuclear translocation after stabilization of microtubules or specific disruption of highly dynamic microtubules. Upon growth hormone treatment, MT-bound STAT5B was rapidly released from microtubules by a dynein-dependent transport to the nucleus. Altogether, our findings indicate that the labile microtubule subpopulation specifically and dynamically organizes STAT5B-mediated growth hormone signaling in hepatic cells.Once bound to specific receptors, a large number of cytokines, growth factors, and hormones act through a sequence of steps allowing the rapid transport of information from the plasma membrane to subcellular targets. This information often results in the phosphorylation of transcription factors that subsequently migrate to the nucleus where they initiate specific gene transcription. How transcription factors are organized as molecular targets downstream of receptor activation and how they move rapidly through the cytoplasm from their activation site to the nucleus often remains unclear. The notion that microtubules (MTs) 1 might be involved in the cytoplasmic activation and/or trafficking of various transcription factors and protein kinases has emerged, as many signal transduction molecules, including transcription factors and protein kinases, have been shown to interact with MTs (1). For example, the glucocorticoid receptor was shown to colocalize with the MT network in mammalian cells (2, 3). The tumor suppressor protein p53 also uses MT tracks to migrate to the nucleus (4). Various protein kinases such as the MAP kinase kinase kinase MLK2 (5) or the MAP kinases ERK1 and ERK2 (6) were also shown to interact or to colocalize with MTs or with microtubule-associated proteins (7).In this study, we investigated the putative involvement of the MT network in GH signaling in the highly differentiated WIF-B hepatic cell line (8, 9...

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Section: Figmentioning

confidence: 99%

STAT5B-mediated Growth Hormone Signaling Is Organized by Highly Dynamic Microtubules in Hepatic Cells

Phung-Koskas

Pilon

Poüs

et al. 2005

Journal of Biological Chemistry

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“…These Armadillo domains were shown by two-hybrid systems to bind to a GTPexchange factor for Rho and Rac, named ASEF, 26,27 to the B56 subunit of PP2A, 28 and to the kinesin superfamily-associated protein 3 (KAP3). 29 We do not yet know if the Armadillo domain in Apc Min/ þ mice is responsible for the attenuation of the tumor production in the colon.…”

Section: Colorectal Cancers In Apcmentioning

confidence: 99%

Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers

Colnot

Niwa‐Kawakita

Hamard

et al. 2004

Laboratory Investigation

168

174

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Murine models of familial adenomatous polyposis harbor a germinal heterozygous mutation on Apc tumor suppressor gene. They are valuable tools for studying intestinal carcinogenesis, as most human sporadic cancers contain inactivating mutations of APC. However, Apc þ /À mice, such as the well-characterized Apc Min/ þ model, develop cancers principally in the small intestine, while humans develop mainly colorectal cancers. We used a Cre-loxP strategy to achieve a new model of germline Apc invalidation in which exon 14 is deleted. We compared the phenotype of these Apc D14/ þ mice to that of the classical Apc Min/ þ . The main phenotypic difference is the shift of the tumors in the distal colon and rectum, often associated with a rectal prolapse. Thus, the severity of the colorectal phenotype is partly due to the particular mutation D14, but also to environmental parameters, as mice raised in conventional conditions developed more colon cancers than those raised in pathogen-free conditions. All lesions, including early lesions, revealed Apc LOH and loss of Apc gene expression. They accumulated b-catenin, overexpressed the b-catenin target genes cyclin D1 and c-Myc, and the distribution pattern of glutamine synthetase, a b-catenin target gene recently identified in the liver, was mosaic in intestinal adenomas. The Apc D14/ þ model is thus a useful new tool for studies on the molecular mechanisms of colorectal tumorigenesis.

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“…39 Lukong and Richard 13 demonstrated that KAP3 knockdown resulted in the suppression of BRK-induced migration of breast cancer cells and that the C-terminal deletion mutant of KAP3 acted as a dominant negative in BRK-induced cell migration. However, another study by Jimbo et al 38 indicated that KAP3-DArm5-transfected Madin-Darby canine kidney cells increased cell migration. These conflicting data indicate that functions of the KAP3-KIF3A-KIF3B complex may depend on cell type.…”

Section: Kinesin-2 Familymentioning

confidence: 94%

“…13 Mutations in the APC gene affect the cell cycle and promote tumor cell growth but suppress differentiation and apoptosis, possibly because the mutant APC protein derived from cancer cells is unable to accumulate efficiently in clusters that are necessary for the interaction of APC with KAP3-KIF3A-KIF3B to form a functional complex. [36][37][38] In addition, conditional inactivation of the KAP3 subunit of the KIF3 complex in neural progenitor cells resulted in embryonic brain tumors. 39 Lukong and Richard 13 demonstrated that KAP3 knockdown resulted in the suppression of BRK-induced migration of breast cancer cells and that the C-terminal deletion mutant of KAP3 acted as a dominant negative in BRK-induced cell migration.…”

Section: Kinesin-2 Familymentioning

confidence: 99%

The role of kinesin family proteins in tumorigenesis and progression

Feng

2010

Cancer

113

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The kinesin superfamily contains a conserved class of microtubule-dependent molecular motor proteins that possess an adenosine triphosphatase activity and motion characteristics. The active movement of kinesins supports several cellular functions, including mitosis, meiosis, and the transport of macromolecules. Mitosis is a process of eukaryotic cell division that involves the division of nuclei, cytoplasm, organelles, and the cell membrane into 2 daughter cells with roughly equivalent portions of these cellular components. Any errors in this process could result in cell death, abnormality (such as gene deletion, chromosome translocation, or duplication), and cancer. Because mitosis is complex and highly regulated, alteration of kinesin expression or function could lead to carcinogenesis. Moreover, because human cancer is a gene-related disease involving abnormal cell growth, targeting kinesins may create a novel strategy for the control of human cancer. Indeed, several such drugs are being tested successfully in the clinic. In this review, the authors discuss in detail the structure and function of kinesins, the correlation of kinesin expression with tumorigenesis and progression, and the development of biomarkers and cancer-targeted therapy involving the kinesin family proteins. Cancer 2010;116:5150-60.

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Identification of a link between the tumour suppressor APC and the kinesin superfamily

Cited by 285 publications

References 19 publications

STAT5B-mediated Growth Hormone Signaling Is Organized by Highly Dynamic Microtubules in Hepatic Cells

STAT5B-mediated Growth Hormone Signaling Is Organized by Highly Dynamic Microtubules in Hepatic Cells

Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers

The role of kinesin family proteins in tumorigenesis and progression

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