TPX2 (TPX2, microtubule-associated, homolog (Xenopus laevis))

2013-03-01   Italia Anna Asteriti , Giulia Guarguaglini 

Institute of Molecular Biology, Pathology, National Research, Council of Italy, c\\\/o Sapienza University of Rome, Via degli Apuli 4, 00185, Rome, Italy





The TPX2 locus is on the q arm of chromosome 20; position 30326904 to 30389603, forward strand (NCBI, 22974).


The 3685 bp mRNA (NCBI Reference Sequence: NM_012112.4) contains 18 exons (16 coding); the processed cDNA is of 2244 bp. Ensembl reports the existence of a second transcript, containing 1 additional exon (ENST00000340513). TPX2 is expressed in proliferating cells; the TPX2 transcript was detected at high levels in human placenta, thymus and testis, while it was barely detectable in brain, heart, lung and pancreas (Manda et al., 1999; Wang et al., 2002; Satow et al., 2010).


No pseudogenes described in humans.



747 aa; MW: 85653 Da.
Human TPX2 was initially identified as a nuclear protein of apparent molecular weight of 100 kDa expressed in proliferating cells, and named p100 (Heidebrecht et al., 1997); it was subsequently re-isolated in the search for mitotic targets of RanGTP as the homolog of X. laevis TPX2 (Gruss et al., 2001).
Human TPX2 harbours distinct functional domains:
- TPX2 is a microtubule-associated protein; both the full length protein and the N-terminus (amino acids 1-352) are able to bind microtubules in vitro (Schatz et al., 2003; Trieselmann et al., 2003). Additional regions in the C-terminus of TPX2 are involved in direct or indirect binding to microtubules in cells (Trieselmann et al., 2003). Domain characterisation of the Xenopus homolog also indicates the presence of one or more microtubule-binding domains in the N-terminus of TPX2; the C-terminal region has no direct affinity for microtubules but is required for localisation to spindle poles (Brunet et al., 2004).
- A non canonical nuclear localisation signal (NLS) centered around amino acids 314-315 (Schatz et al., 2003) mediates binding of TPX2 to importin alpha. Structural work has confirmed the association of the corresponding residues 284-287 in the Xenopus homolog protein to the "minor" NLS-binding site of importin alpha and has shown a second region (residues 327-330 of Xenopus TPX2) contacting the "major" NLS-binding site (Giesecke and Stewart, 2010).
- A KEN box (87-89) degradation motif is required for recognition by APC/CCdh1 (Stewart and Fang, 2005).
- The N-terminal region (residues 1-43; Bayliss et al., 2003) is required for the interaction with, and activation of, the Aurora-A kinase.
- An evolutionary conserved region of 35 amino acids at the C-terminus has been shown both in Xenopus and mouse TPX2 to bind the Eg5 kinesin (Eckerdt et al., 2008; Ma et al., 2010).


TPX2 is expressed in a cell cycle-regulated manner; it appears in S phase and protein levels remain high in G2 and mitosis, until telophase when TPX2 is down-regulated via APC/CCdh1-dependent degradation (Heidebrecth et al., 1997; Gruss et al., 2001; Stewart and Fang, 2005). TPX2 is differentially expressed in tumor vs non-transformed cells (see below).


TPX2 localises to nuclei of interphase cells (S and G2); after nuclear envelope breakdown it associates with spindle microtubules; in late anaphase and telophase it also localises to the spindle mid-zone (Heidebrecht et al., 1997; Gruss et al., 2002; Garrett et al., 2002; figure 1).
Atlas Image
Figure 1. TPX2 localisation in human cells. Immunofluorescence images of U2OS osteosarcoma cells stained with DAPI (blue), anti-alpha-tubulin (green) and anti-TPX2 (red) antibodies show the nuclear localisation of TPX2 in interphase and TPX2 association to spindle microtubules in different mitotic stages. Scale bar: 10 μm.


Spindle assembly: TPX2 is a RanGTP-regulated spindle assembly factor (Gruss et al., 2001). An important contribution to the understanding of the mechanisms through which TPX2 acts in spindle assembly has been provided by studies that made use of the Xenopus egg extract system (Gruss and Vernos, 2004 and references therein).
Evidence obtained in mammalian cells support the notion that TPX2 plays a key role in spindle formation and function. Mitotic functions of TPX2 are negatively regulated by the binding to importin alpha and beta; the presence of RanGTP, by dissociating the complex between TPX2 and import receptors, induces the release of active TPX2 (Gruss et al., 2001). Indeed, excess TPX2 is able to rescue spindle pole organisation defects induced by importin beta overexpression in human cells (Ciciarello et al., 2004), pointing out the functional antagonism between TPX2 and import receptors in spindle assembly.
TPX2 acts in spindle organisation by:
i) its direct ability to induce microtubule assemblies and to bundle microtubules (Schatz et al., 2003);
ii) its targeting function: TPX2 recruits several mitotic regulators to the spindle, i.e. the Aurora-A kinase (Kufer et al., 2002), the kinesins hklp2 (Vanneste et al., 2009; Tanenbaum et al., 2009) and Eg5 (Ma et al., 2011b) and the scaffold attachment factor A (SAF-A; Ma et al., 2011a);
iii) regulation of specific mitotic factors: TPX2 interacts with the Aurora-A kinase and activates it, by stabilising it in the active conformation (Bayliss et al., 2003); in addition, TPX2 modulates Aurora-A protein stability, by counteracting proteasome-dependent Aurora-A degradation (Giubettini et al., 2011). TPX2 also regulates the activity of the Eg5 kinesin: in vitro assays show that TPX2 reduces the rate of Eg5-dependent microtubule gliding and microtubule-microtubule sliding (Ma et al., 2011).
Consistently, its inactivation in cultured mammalian cells impairs microtubule nucleation from chromosomes, and to a lesser extent from centrosomes, as well as organisation of microtubules within the spindle and cohesion of spindle poles (Garrett et al., 2002; Gruss et al., 2002; De Luca et al., 2006; Tulu et al., 2006; Bird and Hyman, 2008).
Neurogenesis in vertebrate brain: Neural progenitor cells in the apical-most region of the neuroepithelium, or ventricular zone, exhibit interkinetic nuclear migration (INM): their nuclei migrate apically in synchrony with cell cycle progression, so that mitosis occurs at the apical surface of the ventricular zone. TPX2 has been recently reported to promote interkinetic nuclear migration in mouse neural cells, by re-organising apical microtubules during the G2 phase (Kosodo et al., 2011).
DNA damage response (DDR): recent data show that TPX2 is involved in DDR to ionising radiations, by modulating the levels of γ-H2AX; TPX2 localises to DNA double strand breaks and interacts with DDR factors such as MDC1 (Neumayer et al., 2012). Previous data suggested a link between TPX2 and DDR: i) TPX2 is a putative substrate of the ATM/ATR kinases, as revealed in a large-scale proteomic screening (Matsuoka et al., 2007); ii) a functional interplay has been shown between Xenopus TPX2, the Aurora-A kinase and the p53 oncosuppressor (Pascreau et al., 2009).


TPX2 orthologs have been identified in all classes of vertebrates, with Xenopus, mouse and human TPX2 being the best characterised. TPX2-like proteins have been described in plants (Vos et al., 2008; Evrard et al., 2009), C. elegans (Ozlü et al., 2005) and Drosophila melanogaster (Goshima, 2011).

Implicated in

Entity name
Various cancers
The TPX2 gene is located on the long arm of chromosome 20, in a region that is frequently amplified in cancer. Growing evidence, described in detail in sections below, indicate that TPX2 levels are increased in tumors and suggest that TPX2 is involved in tumorigenesis. An overall evaluation of TPX2 overexpression in different cancer types can be obtained with the Oncomine database (, which collects data from several microarrays; a recent study using Oncomine shows that TPX2 is significantly overexpressed in about 25% of analyses of tumor vs normal tissues and that it ranks among the first 10% overexpressed genes in the vast majority of cases (Asteriti et al., 2010).
Association of increased TPX2 levels, chromosomal instability (CIN) and cancer has also been highlighted: TPX2 ranked first in a CIN25 signature, the overexpression of which is predictive of poor clinical outcome (Carter et al., 2006). A TPX2 gene signature has also been recently identified as associated with metastatic progression in breast cancer (Hu et al., 2012).
Entity name
Brain cancer
Analysis of astrocytoma tissue samples showed positive TPX2 staining, while TPX2 was not detected in normal brain tissues; in addition, TPX2 expression levels were higher in high-grade, compared with low-grade, astrocytomas. The median survival of patients correlated with TPX2 levels, with high TPX2 being associated with overall poor survival (Li et al., 2010). TPX2 was also identified among 9 genes which are significantly overexpressed in grade III vs grade I meningiomas (Stuart et al., 2011) and among 14 genes with elevated expression in high-risk neuroblastomas with 1p loss and MYCN amplification (Ooi et al., 2012).
Entity name
Oral squamous cell carcinoma
Expression levels of TPX2 were not related with tumor size, lymph node invasion or histopathologic grading (Fenner et al., 2005).
TPX2 expression levels, analysed by RT-PCR (Shigeishi et al., 2009a) or immunohistochemistry (Fenner et al., 2005), were significantly higher compared with normal oral tissues.
Entity name
Salivary gland carcinoma
Levels of TPX2 mRNA were analysed by RT-PCR in 20 human salivary gland carcinomas compared with 6 normal submandibular glands and resulted higher in all tumor samples (Shigeishi et al., 2009b).
Entity name
Lung cancer
Human bronchial epithelial cells malignantly transformed by anti-BPDE (16HBE-C) displayed abnormal levels of phosphorylated TPX2 on tyrosine residues (Zhang et al., 2008).
Three studies indicate the prognostic value of TPX2 overexpression in adenocarcinomas (Kadara et al., 2009; Li et al., 2013) and squamous cell carcinoma (Ma et al., 2006): TPX2 expression is associated with tumor grade and stage and poor survival rates. In particular, TPX2 is among the top genes in prognostic signatures identified as classifiers for overall survival of patients (Kadara et al., 2009; Li et al. 2013).
Several studies report increased TPX2 expression levels in primary lung tumors (adenocarcinomas, squamous cell carcinoma, small cell carcinoma) and lung cancer cell lines, compared to controls (Manda et al., 1999; Tonon et al., 2005; Ma et al., 2006; Zhang et al., 2008; Kadara et al., 2009; Li et al., 2013).
Entity name
Colon cancer
TPX2 overexpression in colorectal cancer was observed by suppression subtractive hybridisation (SSH) method applied to a primary stage III rectal adenocarcinoma and the matched non-neoplastic mucosa (Hufton et al., 1999). In addition, protein levels of TPX2 and of its partner Aurora-A correlate significantly with chromosome 20q DNA copy number status: TPX2 and Aurora-A are therefore implicated in the 20q amplicon-driven progression of colorectal adenoma to carcinoma (Sillars-Hardebol et al., 2012).
Entity name
Liver cancer
The TPX2 transcript is expressed at high levels in hepatocellular carcinomas, compared with weak expression in paired normal tissues (Wang et al., 2002; Satow et al., 2010).
Entity name
Pancreatic cancer
Increased expression of TPX2 was associated with poor survival and significantly correlated with histological grade in two independent cohorts (from Germany and Maryland; Zhang et al., 2012). When cohorts were combined, and stratified by resection margin status (positive vs negative), TPX2 was associated with cancer-specific mortality in resection margin-positive patients and with prognosis in resection margin-negative patients.
Low copy-number amplification of TPX2, associated with increased mRNA and protein levels, was observed in pancreatic cancer cell lines (Warner et al., 2009); the TPX2 gene is also included in an amplicon identified by microarray analysis of pancreatic ductal adenocarcinoma (Tonon et al., 2005). Immunohistochemical staining of tissue microarrays showed increased TPX2 levels in pancreatic tumors compared with the normal counterparts (Warner et al., 2009; Zhang et al., 2012).
Entity name
Ovarian cancer
The Aurora-A kinase, which interacts with, and is regulated by, TPX2 is also differentially expressed in ovarian carcinomas vs adenomas (Scharer et al., 2008).
A comparative analysis revealed a stronger (15 to 27 fold) overexpression of TPX2 in primary ovarian carcinomas compared with non-malignant adenomas (Scharer et al., 2008).
A high resolution genome wide copy number analysis combined with matching expression data from primary epithelial ovarian carcinomas of various histotypes showed that TPX2 is among the most significantly differentially expressed genes in a chromosome 20 region frequently amplified in ovarian cancer (Ramakrishna et al., 2010).
Entity name
Cervical cancer
TPX2 expression levels in cervical squamous cell carcinoma positively correlate with tumor stage and grade, and lymph node metastasis (Chang et al., 2012).
Copy number increase of chromosome 20q, where the TPX2 gene is located, is frequently observed in cervical cancers; indeed TPX2 is reported among the 26 genes that are significantly overexpressed as consequence of 20q gain (Scotto et al., 2008). TPX2 mRNA and protein are highly expressed in cervical cancer, while its expression is almost absent in normal cervical tissues (Chang et al., 2012).
Entity name
Bladder cancer
RNA microarrays and RT-PCR analyses showed significant upregulation of TPX2 in urothelial carcinomas of the bladder compared with normal urothelium (Zhou et al., 2013).
Entity name
Mesothelial tumors
Immunostaining of malignant mesothelioma samples compared to benign reactive mesothelial hyperplasia showed significant overexpression of TPX2 in malignant samples, suggesting that TPX2 represents a useful marker in this respect (Taheri et al., 2008).


Pubmed IDLast YearTitleAuthors
207086552010The Aurora-A/TPX2 complex: a novel oncogenic holoenzyme?Asteriti IA et al
145803372003Structural basis of Aurora-A activation by TPX2 at the mitotic spindle.Bayliss R et al
186631422008Building a spindle of the correct length in human cells requires the interaction between TPX2 and Aurora A.Bird AW et al
153856252004Characterization of the TPX2 domains involved in microtubule nucleation and spindle assembly in Xenopus egg extracts.Brunet S et al
169213762006A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers.Carter SL et al
223071082012The TPX2 gene is a promising diagnostic and therapeutic target for cervical cancer.Chang H et al
155724122004Importin beta is transported to spindle poles during mitosis and regulates Ran-dependent spindle assembly factors in mammalian cells.Ciciarello M et al
164185752006A functional interplay between Aurora-A, Plk1 and TPX2 at spindle poles: Plk1 controls centrosomal localization of Aurora-A and TPX2 spindle association.De Luca M et al
183721772008Spindle pole regulation by a discrete Eg5-interacting domain in TPX2.Eckerdt F et al
197047132009Plant TPX2 and related proteins.Evrard JL et al
163627842005Restricted-expressed proliferation-associated protein (Repp86) expression in squamous cell carcinoma of the oral cavity.Fenner M et al
124773962002hTPX2 is required for normal spindle morphology and centrosome integrity during vertebrate cell division.Garrett S et al
203351812010Novel binding of the mitotic regulator TPX2 (target protein for Xenopus kinesin-like protein 2) to importin-alpha.Giesecke A et al
211478532011Control of Aurora-A stability through interaction with TPX2.Giubettini M et al
221405192011Identification of a TPX2-like microtubule-associated protein in Drosophila.Goshima G et al
111632422001Ran induces spindle assembly by reversing the inhibitory effect of importin alpha on TPX2 activity.Gruss OJ et al
154521382004The mechanism of spindle assembly: functions of Ran and its target TPX2.Gruss OJ et al
123890332002Chromosome-induced microtubule assembly mediated by TPX2 is required for spindle formation in HeLa cells.Gruss OJ et al
92074571997p100: a novel proliferation-associated nuclear protein specifically restricted to cell cycle phases S, G2, and M.Heidebrecht HJ et al
223084182012Integrated cross-species transcriptional network analysis of metastatic susceptibility.Hu Y et al
106016421999A profile of differentially expressed genes in primary colorectal cancer using suppression subtractive hybridization.Hufton SE et al
196384912009Identification of gene signatures and molecular markers for human lung cancer prognosis using an in vitro lung carcinogenesis system.Kadara H et al
214418952011Regulation of interkinetic nuclear migration by cell cycle-coupled active and passive mechanisms in the developing brain.Kosodo Y et al
121770452002Human TPX2 is required for targeting Aurora-A kinase to the spindle.Kufer TA et al
205998062010Expression of targeting protein for Xenopus kinesin-like protein 2 is associated with progression of human malignant astrocytoma.Li B et al
233574622013Network-based approach identified cell cycle genes as predictor of overall survival in lung adenocarcinoma patients.Li Y et al
212423132011The nuclear scaffold protein SAF-A is required for kinetochore-microtubule attachment and contributes to the targeting of Aurora-A to mitotic spindles.Ma N et al
219694682011TPX2 regulates the localization and activity of Eg5 in the mammalian mitotic spindle.Ma N et al
201103502010Poleward transport of TPX2 in the mammalian mitotic spindle requires dynein, Eg5, and microtubule flux.Ma N et al
164890642006Expression of targeting protein for xklp2 associated with both malignant transformation of respiratory epithelium and progression of squamous cell lung cancer.Ma Y et al
105126751999Identification of genes (SPON2 and C20orf2) differentially expressed between cancerous and noncancerous lung cells by mRNA differential display.Manda R et al
234442242013Functional genetic screens identify genes essential for tumor cell survival in head and neck and lung cancer.Martens-de Kemp SR et al
175253322007ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.Matsuoka S et al
174833532007Identification of Ras-related nuclear protein, targeting protein for xenopus kinesin-like protein 2, and stearoyl-CoA desaturase 1 as promising cancer targets from an RNAi-based screen.Morgan-Lappe SE et al
230455262012Targeting protein for xenopus kinesin-like protein 2 (TPX2) regulates γ-histone 2AX (γ-H2AX) levels upon ionizing radiation.Neumayer G et al
223376472012Segmental chromosome aberrations converge on overexpression of mitotic spindle regulatory genes in high-risk neuroblastoma.Ooi WF et al
160540302005An essential function of the C. elegans ortholog of TPX2 is to localize activated aurora A kinase to mitotic spindles.Ozlü N et al
191219982009Phosphorylation of p53 is regulated by TPX2-Aurora A in xenopus oocytes.Pascreau G et al
203866952010Identification of candidate growth promoting genes in ovarian cancer through integrated copy number and expression analysis.Ramakrishna M et al
203888462010Combined functional genome survey of therapeutic targets for hepatocellular carcinoma.Satow R et al
190772372008Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells.Scharer CD et al
127278732003Importin alpha-regulated nucleation of microtubules by TPX2.Schatz CA et al
185067482008Identification of copy number gain and overexpressed genes on chromosome arm 20q by an integrative genomic approach in cervical cancer: potential role in progression.Scotto L et al
191485052009Expression of TPX2 in salivary gland carcinomas.Shigeishi H et al
222076302012TPX2 and AURKA promote 20q amplicon-driven colorectal adenoma to carcinoma progression.Sillars-Hardebol AH et al
162878632005Anaphase-promoting complex/cyclosome controls the stability of TPX2 during mitotic exit.Stewart S et al
211573822011Identification of gene markers associated with aggressive meningioma by filtering across multiple sets of gene expression arrays.Stuart JE et al
183842222008The diagnostic value of Ki-67 and repp86 in distinguishing between benign and malignant mesothelial proliferations.Taheri ZM et al
198186182009Kif15 cooperates with eg5 to promote bipolar spindle assembly.Tanenbaum ME et al
159833842005High-resolution genomic profiles of human lung cancer.Tonon G et al
146002642003Ran modulates spindle assembly by regulating a subset of TPX2 and Kid activities including Aurora A activation.Trieselmann N et al
165277512006Molecular requirements for kinetochore-associated microtubule formation in mammalian cells.Tulu US et al
227619062012High-throughput transcriptomic and RNAi analysis identifies AIM1, ERGIC1, TMED3 and TPX2 as potential drug targets in prostate cancer.Vainio P et al
198186192009The role of Hklp2 in the stabilization and maintenance of spindle bipolarity.Vanneste D et al
189410542008The plant TPX2 protein regulates prospindle assembly before nuclear envelope breakdown.Vos JW et al
120974192002Large scale identification of human hepatocellular carcinoma-associated antigens by autoantibodies.Wang Y et al
198614552009Validation of TPX2 as a potential therapeutic target in pancreatic cancer cells.Warner SL et al
223636582012DPEP1 inhibits tumor cell invasiveness, enhances chemosensitivity and predicts clinical outcome in pancreatic ductal adenocarcinoma.Zhang G et al
187230712008TPX2 in malignantly transformed human bronchial epithelial cells by anti-benzo[a]pyrene-7,8-diol-9,10-epoxide.Zhang L et al
234036332013The investigational Aurora kinase A inhibitor MLN8237 induces defects in cell viability and cell-cycle progression in malignant bladder cancer cells in vitro and in vivo.Zhou N et al

Other Information

Locus ID:

NCBI: 22974
MIM: 605917
HGNC: 1249
Ensembl: ENSG00000088325


dbSNP: 22974
ClinVar: 22974
TCGA: ENSG00000088325


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G2-G2/M phasesREACTOMER-HSA-453274
G2/M TransitionREACTOMER-HSA-69275
AURKA Activation by TPX2REACTOMER-HSA-8854518
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Activity through PhosphorylationREACTOMER-HSA-6804756

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
121770452002Human TPX2 is required for targeting Aurora-A kinase to the spindle.180
123890332002Chromosome-induced microtubule assembly mediated by TPX2 is required for spindle formation in HeLa cells.108
211873292010Protein phosphatase 6 regulates mitotic spindle formation by controlling the T-loop phosphorylation state of Aurora A bound to its activator TPX2.78
186631422008Building a spindle of the correct length in human cells requires the interaction between TPX2 and Aurora A.72
245569982014TPX2: of spindle assembly, DNA damage response, and cancer.58
222076302012TPX2 and AURKA promote 20q amplicon-driven colorectal adenoma to carcinoma progression.54
124773962002hTPX2 is required for normal spindle morphology and centrosome integrity during vertebrate cell division.48
248676432014Molecular mechanism of Aurora A kinase autophosphorylation and its allosteric activation by TPX2.48
264144022015Complementary activities of TPX2 and chTOG constitute an efficient importin-regulated microtubule nucleation module.45
162878632005Anaphase-promoting complex/cyclosome controls the stability of TPX2 during mitotic exit.40


Italia Anna Asteriti ; Giulia Guarguaglini

TPX2 (TPX2, microtubule-associated, homolog (Xenopus laevis))

Atlas Genet Cytogenet Oncol Haematol. 2013-03-01

Online version: