Differential interaction of Enigma protein with the two RET isoforms.
The receptor tyrosine kinase RET, with a known role in embryonic development and in human pathologies, is alternatively spliced to yield at least two functional isoforms, which differ only in their carboxyl terminal. Enigma protein is a member of the PDZ-LIM family and is known to interact with the short isoform of RET/PTC2, a chimeric oncoprotein isolated from papillary thyroid carcinoma. Here, we show that Enigma also interacts in intact cells with the short isoform of RET-wt and of its pathologic mutants associated to MEN2 syndromes, RET-C634R and RET-M918T. In contrast, Enigma binds all the corresponding RET long isoforms very poorly and colocalizes with short but not long RET/PTC2 isoforms. The RET docking tyrosine for Enigma is the last but one before the divergence between the two isoforms and we demonstrated that short-isoform-specific amino acid residues +2 to +4 to this tyrosine are required for the interaction of RET/PTC2 with Enigma.
Borrello
Maria Grazia
MG
Department of Experimental Oncology, Research Unit #3, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. mariagrazia.borrello@istitutotumori.mi.it
Mercalli
Elena
E
Perego
Carla
C
Degl'Innocenti
Debora
D
Ghizzoni
Simona
S
Arighi
Elena
E
Eroini
Barbara
B
Rizzetti
Maria Grazia
MG
Pierotti
Marco A
MA
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D002460:Cell Line; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D051379:Mice; D008969:Molecular Sequence Data; D011233:Precipitin Tests; D020033:Protein Isoforms / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C484380:PDLIM7 protein, human; C484381:Pdlim7 protein, mouse; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse