Disease relevance of TPM3

• The TPM3 gene has been previously found in papillary thyroid carcinomas as a fusion partner with the TRK kinase gene [1].
• A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation [1].
• De novo missense mutation in a constitutively expressed exon of the slow alpha-tropomyosin gene TPM3 associated with an atypical, sporadic case of nemaline myopathy [2].
• In the 'spontaneous' tumours, only one of the 14 papillary carcinomas and one of the four in vitro culture cell lines, derived from a papillary carcinoma, presented a NTRK1 rearrangement also with the TPM3 gene [3].
• TPM3/PDGFRB fusion transcript and its reciprocal in chronic eosinophilic leukemia [4].

High impact information on TPM3

• A mutation in the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy [5].
• The amino acid sequence of TC22 isoform is identical to isoform 5 (hTM5) apart from the C terminal domain, amino acids 222-247 coding the exon 9 [6].
• RESULTS: The major hTM isoforms present in colonic and jejunal epithelial cells are hTM5 and hTM4, whereas intestinal smooth muscle contains the hTM1-3 isoforms [7].
• Immunofluorescence microscopy reveals that stably transfected CHO cells incorporate force-expressed hTM3 and hTM5 into stress fibers with no significant effect on general cell morphology, microfilament organization or cytokinesis [8].
• A closely related chimeric isoform hTM5/2, which differs only in the internal, alternatively spliced exon also produces defects in cytokinesis, suggesting that normal TM function may involve coordination between the amino and carboxy terminal regions [8].

Chemical compound and disease context of TPM3

• In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded [9].
• Enadoline may yet find some application against ischaemic stroke and severe head injury, presumably in comatose patients in whom psychiatric side-effects are taken to be immaterial, while apadoline and TRK 820 remain in Phase II clinical testing against cancer pain [10].

Biological context of TPM3

• Using a polymerase chain reaction (PCR)-based technique to walk on chromosome 2 from the known ALK gene across the breakpoint, we showed that the gene involved at 1q25 is TPM3, encoding a nonmuscular tropomyosin [1].
• The non-muscle isoform of the TPM3 gene product becomes fused to a gene product from the tyrosine kinase receptor gene (NTRK1), previously localized to 1q23-->q24, to generate an active oncogene [11].
• Two sequence tagged sites spanning three exons and two introns in the carboxy coding region of the gene were used to localize TPM3 to 1q22-->q23 by fluorescence in situ hybridization [11].
• In all of them, the illegitimate recombination involved the 611-bp NTRK1 intron placed upstream of the transmembrane domain and the TPM3 intron located between exons 7 and 8 [12].
• One proband, who was not noted to have any weakness neonatally, but who died at 21 months of age, was shown to be homozygous for a single strand conformation polymorphism (SSCP) in skeletal-muscle-specific exon 1 of TPM3 [13].

Anatomical context of TPM3

• We showed that TPM3 is constitutively expressed in lymphoid cell lines, suggesting that, in these t(1;2)-bearing ALCL cases, the TPM3 gene contributes an active promoter for ALK expression [1].
• This approach accurately identified the nucleophosmin (NPM)-ALK fusion protein in an anaplastic large cell lymphoma (ALCL)-derived cell line carrying the t(2;5)(p23;q35), and the TPM3-ALK in a clinical biopsy of inflammatory myofibroblastic tumor (IMT) carrying the t(1;2)(q21;p23) [14].
• Mutations in the human TPM3 gene encoding gamma-tropomyosin (alpha-tropomyosin-slow) expressed in slow skeletal muscle fibers cause nemaline myopathy [15].
• Our results concerning the radiation-associated tumours showed that only rearrangements between NTRK1 and TPM3 genes (TRK oncogene) were detected in 2/14 papillary carcinomas and in one lymph-node metastasis of one of these papillary thyroid carcinomas [3].
• In sodium dodecyl sulfate-polyacrylamide gel electrophoresis, hTM5 comigrated with the slower TM major species in erythrocyte membranes, and hTM5b comigrated with the faster TM major species [16].

Associations of TPM3 with chemical compounds

• Platelet malonyldialdehyde (MDA) formation in the presence of N-ethyl maleimide (NEM 1 mM) or thrombin (0.5 u/ml) was used as an indicator of platelet prostaglandin synthesis [17].
• RESULTS: At surgery, in rectal samples, hTM5 expression was strong in all epithelial cells including the luminal surface, whereas in ileal samples hTM5 was not expressed or focally expressed only in the goblet cells [18].
• Surplus sarcoplasmic and/or intranuclear nemaline bodies have been related to mutant tropomyosin-3, actin and nebulin genes [19].
• In UC, hTM5 IgG were higher in p-ANCA+ than in ANCA- patients (P=0.04) [20].
• LS-180 cells spontaneously released hTM5 as well as CEP into the culture medium that was significantly stimulated by a calcium ionophore, A23187, but inhibited by phorbol-12-myristate-13-acetate, monensin and methylamine [21].

Physical interactions of TPM3

• Erythrocyte tropomodulin binds to the N-terminus of hTM5, a tropomyosin isoform encoded by the gamma-tropomyosin gene [22].

Other interactions of TPM3

• In previously reported studies we have demonstrated that NTRK1 oncogenic activation involves two genes, TPM3 and TPR, both localized similarly to the receptor tyrosine kinase, on the q arm of chromosome 1 [23].
• METHODS: Results of 164 muscle biopsies from 124 Australian and North American patients with primary nemaline myopathy were reviewed, including biopsies from 19 patients with nemaline myopathy due to alpha-actin (ACTA1) mutations and three with mutations in alpha-tropomyosin(SLOW) (TPM3) [24].
• We have previously cloned the human tropomodulin complementary DNA and identified human TM isoform 5 (hTM5), a product of the gamma-TM gene, as one of the major TM isoforms in erythrocytes [16].
• Tropomyosin (TM), a component of the thin filament of the sarcomere, is encoded by a four-member multigene family: alpha-TM, beta-TM, TPM 3, and TPM 4 [25].
• Among them, peroxiredoxin 1 (PRDX1) expression level was significantly increased from stage I to III, and had a slight decrease at stage IV; whereas, a lasting decrease in the expression level of tropomyosins 3 (TPM3), was observed with the malignant progression from I stage to IV stage [26].

Analytical, diagnostic and therapeutic context of TPM3

• A sequence analysis of the genomic regions involved in the rearrangements between TPM3 and NTRK1 genes producing TRK oncogenes in papillary thyroid carcinomas [12].
• To investigate the frequency of TRK protooncogene rearrangement in Chinese thyroid tumors, we performed reverse transcriptase polymerase chain reaction to amplify specific TRK rearrangement transcripts [27].
• Microinjection of hTM5, a low molecular mass isoform had no effect on organelle distribution [28].
• The chromosomal localization of hTMnm, a gene coding for a cytoskeletal tropomyosin non-muscle isoform involved in the activation of the TRK proto-oncogene in various human tumors, was determined by Southern blot analysis of a panel of human-rodent somatic cell hybrids [29].
• Co-immunoprecipitation experiments revealed that hTM5 forms a complex with CEP [21].

References