An Essential Function of the C. elegans Ortholog of TPX2 Is to Localize Activated Aurora A Kinase to Mitotic Spindles

Özlü, Nurhan; Srayko, Martin; Kinoshita, Kazuhisa; Habermann, Bianca; O’Toole, Eileen; Müller‐Reichert, Thomas; Schmalz, Natalie; Desai, Arshad; Hyman, Anthony A.

doi:10.1016/j.devcel.2005.07.002

Cited by 106 publications

(114 citation statements)

References 47 publications

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“…This result is consistent with the earlier observations that, both in egg extract and in cells, bipolar spindle formation can proceed without centrosomes, presumably via the chromatin/RanGTP/TPX2-mediated pathway (24,30,31). By contrast, and as expected (13,14,25,27,32), TPX2-depleted extract was inactive in RanGTP-driven MT assembly, while supporting AurA recruitment to and MT nucleation by centrosomes (Fig. 2F, i and iii and Fig.…”

Section: Resultssupporting

confidence: 93%

“…2E), confirming that a minor fraction of endogenous AurA is bound to Cep192 and TPX2 in distinct complexes. Cep192 depletion did not affect the assembly of RanGTP-induced MT asters or AurA targeting to MTs, which are TPX2-dependent processes (13,14,25) (Fig. 2F, iii, quantified in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…AurA activation depends on the phosphorylation of threonine (T) 288/295 (in human/Xenopus AurA, respectively) in its kinase activation loop (9,10) and, in one specific mitotic setting, on the binding of targeting protein for Xklp2 (TPX2), a MTnucleating protein (10)(11)(12). TPX2, when released from importin by RanGTP, activates AurA (both allosterically and by protecting T288/T295 from dephosphorylation) (10)(11)(12) and targets AurA to spindle MTs (13,14). The AurA-TPX2 complex participates in spindle assembly promoted by chromatin/RanGTP but not by centrosomes and in setting a proper spindle length (11,15,16).…”

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confidence: 99%

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Centrosomal protein of 192 kDa (Cep192) promotes centrosome-driven spindle assembly by engaging in organelle-specific Aurora A activation

Joukov

Nicolo

Rodriguez

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

102

187

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Centrosomes are primary microtubule (MT)-organizing centers (MTOCs). During mitosis, they dramatically increase their size and MT-nucleating activity and participate in spindle assembly from spindle poles. These events require the serine/threonine kinase, Aurora A (AurA), and the centrosomal protein of 192 kDa (Cep192)/spindle defective 2 (Spd-2), but the underlying mechanism remains unclear. We have found that Cep192, unlike targeting protein for Xklp2 (TPX2), a known MT-localizing AurA activator, is an AurA cofactor in centrosome-driven spindle assembly. Cep192, through a direct interaction, targets AurA to mitotic centrosomes where the locally accumulating AurA forms homodimers or oligomers. The dimerization of endogenous AurA, in the presence of bound Cep192, triggers potent kinase activation that, in turn, drives MT assembly. Depletion of Cep192 or specific interference with AurA-Cep192 binding did not prevent AurA oligomerization on MTs but abrogated AurA recruitment to centrosomes and its activation by either sperm nuclei or anti-AurA antibody (αAurA)-induced dimerization. In these settings, MT assembly by both centrosomes and αAurA-coated beads was also abolished or severely compromised. Hence, Cep192 activates AurA by a mechanism different from that previously described for TPX2. The Cep192-mediated mechanism maximizes AurA activity at centrosomes and appears essential for the function of these organelles as MTOCs.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Centrosomal protein of 192 kDa (Cep192) promotes centrosome-driven spindle assembly by engaging in organelle-specific Aurora A activation

Joukov

Nicolo

Rodriguez

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

102

187

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“…As a microtubule-associated protein, TPX2 tightly adheres to the mitotic spindle in mitotic cells (28). In certain tumors, overexpression of TPX2 results in centrosome amplification and heteroploidy formation (29,30). TPX2 has been demonstrated to be upregulated in salivary gland carcinoma, lung carcinoma and ovarian cancer, with its abnormal expression involved in tumorigenesis and malignant progression (15,16,31).…”

Section: Discussionmentioning

confidence: 99%

TPX2 in human clear cell renal carcinoma: Expression, function and prognostic significance

et al. 2016

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Abstract. Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated protein. TPX2 is considered to be an important gene in tumorigenesis; however, the particular function of TPX2 in the development of human renal cell carcinoma (RCC) is unknown. In the present study, the expression, function and prognostic significance of TPX2 in human RCC was analyzed. A total of 286 tissue samples from patients with RCC who had undergone nephrectomies were utilized. Subsequently, the expression of TPX2 protein was investigated using immunohistochemistry and western blotting, and TPX2 mRNA expression was examined using reverse transcription-quantitative polymerase chain reaction. To establish the effect of TPX2 on the proliferation and invasion of the RCC cells, TPX2 expression was increased by stable transfection with a TPX2 vector and TPX2 expression was decreased using small interfering RNA. Proliferation of the RCC cells was analyzed using a WST-1 assay and an animal xenograft model with BALB/c nude mice, whilst invasion of the RCC cells was examined using a Matrigel-coated invasion chamber. It was demonstrated that TPX2 expression was significantly higher in the RCC tissues compared with normal kidney tissues (P<0.05). Furthermore, TPX2 expression was associated with tumor size, histological grade and tumor stage (P<0.05), and was observed to markedly increase the proliferation and invasion of the RCC cells. It may be concluded that the expression of TPX2 is significantly upregulated in RCC tissue, subsequently increasing the proliferative and invasive ability of RCC cells. Therefore, the protein may serve as a therapeutic target and independent prognostic factor in the treatment of human RCC.

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“…The Aurora A(S155R) mutation alters the activity and regulation of the kinase, but how could this contribute to the development or survival of a cancerous cell? Studies in human cells and Caenorhabditis elegans in which mutants of TPX2 or TPX-L that did not bind Aurora A replaced the endogenous protein showed that elimination of the interaction resulted in defective mitotic spindles (43,44). In the absence of the interaction with TPX2, Aurora A is localized exclusively to the centrosomes (43,44).…”

Section: Discussionmentioning

confidence: 99%

A Cancer-associated Aurora A Mutant Is Mislocalized and Misregulated Due to Loss of Interaction with TPX2

Bibby

Tang²,

Faisal

et al. 2009

Journal of Biological Chemistry

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Mutations in protein kinases can drive cancer through alterations of the kinase activity or by uncoupling kinase activity from regulation. Changes to protein expression in Aurora A, a mitotic Ser/Thr kinase, are associated with the development of several human cancers, but the effects of somatic cancer-associated mutations have not been determined. In this study we show that Aurora A kinase activity is altered in different ways in three somatic cancer-associated mutations located within the catalytic domain; Aurora A(V174M) shows constitutively increased kinase activity, Aurora A(S155R) activity is decreased primarily due to misregulation, and Aurora A(S361*) activity is ablated due to loss of structural integrity. These alterations suggest vastly different mechanisms for the role of these three mutations in human cancer. We have further characterized the Aurora A(S155R) mutant protein, found that its reduced cellular activity and mislocalization are due to loss of interaction with TPX2, and deciphered the structural basis of the disruption at 2.5 Å resolution. Previous studies have shown that disruption of the Aurora A/TPX2 interaction results in defective spindles that generate chromosomal abnormalities. In a panel of 40 samples from microsatellite instability-positive colon cancer patients, we found one example in which the tumor contained only Aurora A(S155R), whereas the normal tissue contained only wild-type Aurora A. We propose that the S155R mutation is an example of a somatic mutation associated with this tumor type, albeit at modest frequency, that could promote aneuploidy through the loss of regulated interactions between Aurora A and its protein partners.Aurora A is a centrosome and mitotic spindle-associated, cell cycle-regulated serine/threonine kinase and is a key regulator of mitosis (1-5). The protein levels and the activity of Aurora A peak at G 2 and during mitosis, whereas its expression is low in resting cells (1, 6). The Aurora A gene is located on human chromosome 20q13, a region that has been found to be amplified in a variety of human tumors (7). Overexpression of Aurora A induces abnormal spindle formation, leading to prolonged mitosis and polyploidy (8). Aurora A was first described in human cancer cell lines but has subsequently been found to be overexpressed in a broad range of human tumors, including primary colorectal carcinoma, gliomas, breast, ovarian, and pancreatic cancers (1, 9 -12).The association of Aurora A with cancer has prompted many studies that have revealed details of the function and regulation of the kinase. Bona fide substrates that are regulated by Aurora A phosphorylation include TACC3, Plk1, Eg5, and p53 (13-22). The catalytic activity of Aurora A is activated by phosphorylation on Thr-288 in its activation loop and by interaction with partner proteins such as TPX2, Ajuba, and HEF1 (13, 23-27). Aurora A is deactivated by dephosphorylation of Thr-288 by protein phosphatase 1 (PP1), 4 which is prevented by TPX2 (24, 25, 27). Aurora A and TPX2 are both degraded by ...

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An Essential Function of the C. elegans Ortholog of TPX2 Is to Localize Activated Aurora A Kinase to Mitotic Spindles

Cited by 106 publications

References 47 publications

Centrosomal protein of 192 kDa (Cep192) promotes centrosome-driven spindle assembly by engaging in organelle-specific Aurora A activation

Centrosomal protein of 192 kDa (Cep192) promotes centrosome-driven spindle assembly by engaging in organelle-specific Aurora A activation

TPX2 in human clear cell renal carcinoma: Expression, function and prognostic significance

A Cancer-associated Aurora A Mutant Is Mislocalized and Misregulated Due to Loss of Interaction with TPX2

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