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]