Tpr-met fusion protein

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

Contents

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]

Related Research Articles

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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. doi:10.1038/sj.onc.1210522. PMID   17533376.
  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. doi:10.1128/mcb.7.2.921. ISSN   0270-7306. PMC   365151 . PMID   3821733.
  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. Bibcode:1987PNAS...84.6379P. doi: 10.1073/pnas.84.18.6379 . ISSN   0027-8424. PMC   299079 . PMID   2819873.
  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. doi:10.1128/mcb.13.11.6711. ISSN   0270-7306. PMC   364734 . PMID   8413267.
  5. ↑ Peschard, P.; Park, M. (2007-02-26). "From Tpr-Met to Met, tumorigenesis and tubes". Oncogene. 26 (9): 1276–1285. doi:10.1038/sj.onc.1210201. ISSN   0950-9232. PMID   17322912.
  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. doi:10.1074/jbc.M610916200. ISSN   0021-9258. PMID   17194700.
  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 . PMC   5344230 . PMID   28536403.
  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 (31): 31378–98. doi:10.18632/oncotarget.5145. ISSN   1949-2553. PMC   4741613 . PMID   26384300.
  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. Bibcode:2011PLoSO...614675L. doi: 10.1371/journal.pone.0014675 . ISSN   1932-6203. PMC   3036588 . PMID   21347410.


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