Tpr-met fusion protein

Tpr-Met fusion protein is an oncogene fusion protein consisting of TPR and MET.[1]

Structure

Tpr-Met was generated following a chromosomal rearrangement induced by the treatment of a human osteogenic sarcoma cell line with the carcinogen N-methyl-N'-nitronitrosoguanidine. The genomic rearrangement fuses two genetic loci,translocated promoter region, from chromosome 1q25 which encodes a dimerization leucine zipper motif, and MET, from chromosome 7q31 which contributes the kinase domain and carboxy-terminus of the Met RTK.[2][3] The resulting 65 kDa cytoplasmic Tpr-Met oncoprotein forms a dimer mediated through the Tpr leucine zipper.[4]

The Tpr-Met fusion protein lacks the extracellular, transmembrane and juxtamembrane domains of c-Met receptor, and has gained the Tpr dimerization motif, which allows constitutive and ligand-independent activation of the kinase. The loss of juxtamembrane sequences, necessary for the negative regulation of kinase activity and receptor degradation, prolongs duration of Met signalling.[5]

Experimental evidences

Effects in muscle

Skeletal muscle

Specific expression of Tpr-Met in terminally-differentiated skeletal muscle causes muscle wasting in vivo and exerts anti-differentiation effects in terminally differentiated myotubes.[6][7] Constitutive activation of MET signaling has been suggested to cause defects in myogenic differentiation, contributing to rhabdomyosarcoma development and progression.[8]

Cardiac muscle

In a transgenic model, cardiac-specific expression of Tpr-Met oncogene during postnatal life causes heart failure with early-onset.[9]

References

  1. ↑ Mak HH, Peschard P, Lin T, Naujokas MA, Zuo D, Park M (2007). "Oncogenic activation of the Met receptor tyrosine kinase fusion protein, Tpr-Met, involves exclusion from the endocytic degradative pathway". Oncogene. 26 (51): 7213–21. PMID 17533376. doi:10.1038/sj.onc.1210522.
  2. ↑ Dean, M.; Park, M.; Vande Woude, G. F. (1987-02-01). "Characterization of the rearranged tpr-met oncogene breakpoint". Molecular and Cellular Biology. 7 (2): 921–924. ISSN 0270-7306. PMC 365151 Freely accessible. PMID 3821733. doi:10.1128/mcb.7.2.921.
  3. ↑ Park, M.; Dean, M.; Kaul, K.; Braun, M. J.; Gonda, M. A.; Vande Woude, G. (1987-09-01). "Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors". Proceedings of the National Academy of Sciences of the United States of America. 84 (18): 6379–6383. ISSN 0027-8424. PMC 299079 Freely accessible. PMID 2819873. doi:10.1073/pnas.84.18.6379.
  4. ↑ Rodrigues, G. A.; Park, M. (1993-11-01). "Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase". Molecular and Cellular Biology. 13 (11): 6711–6722. ISSN 0270-7306. PMC 364734 Freely accessible. PMID 8413267. doi:10.1128/mcb.13.11.6711.
  5. ↑ Peschard, P.; Park, M. (2007-02-26). "From Tpr-Met to Met, tumorigenesis and tubes". Oncogene. 26 (9): 1276–1285. ISSN 0950-9232. PMID 17322912. doi:10.1038/sj.onc.1210201.
  6. ↑ Crepaldi, Tiziana; Bersani, Francesca; Scuoppo, Claudio; Accornero, Paolo; Prunotto, Chiara; Taulli, Riccardo; Forni, Paolo E.; Leo, Christian; Chiarle, Roberto (2007-03-02). "Conditional activation of MET in differentiated skeletal muscle induces atrophy". The Journal of Biological Chemistry. 282 (9): 6812–6822. ISSN 0021-9258. PMID 17194700. doi:10.1074/jbc.M610916200.
  7. ↑ Sala, Valentina; Gallo, Simona; Gatti, Stefano; Vigna, Elisa; Ponzetto, Antonio; Crepaldi, Tiziana (2015-02-12). "Anti-Differentiation Effect of Oncogenic Met Receptor in Terminally-Differentiated Myotubes". Biomedicines. 3 (1): 124–137. doi:10.3390/biomedicines3010124.
  8. ↑ Skrzypek, Klaudia; Kusienicka, Anna; Szewczyk, Barbara; Adamus, Tomasz; Lukasiewicz, Ewa; Miekus, Katarzyna; Majka, Marcin (2015-09-08). "Constitutive activation of MET signaling impairs myogenic differentiation of rhabdomyosarcoma and promotes its development and progression". Oncotarget. 6: 31378–98. ISSN 1949-2553. PMC 4741613 Freely accessible. PMID 26384300. doi:10.18632/oncotarget.5145.
  9. ↑ Leo, Christian; Sala, Valentina; Morello, Mara; Chiribiri, Amedeo; Riess, Ilan; Mancardi, Daniele; Schiaffino, Stefano; Ponzetto, Carola; Crepaldi, Tiziana (2011-02-09). "Activated Met Signalling in the Developing Mouse Heart Leads to Cardiac Disease". PLoS ONE. 6 (2): e14675. ISSN 1932-6203. PMC 3036588 Freely accessible. PMID 21347410. doi:10.1371/journal.pone.0014675.


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