TY - JOUR
T1 - Gain of function mutations of RTK conserved residues display differential effects on NTRK1 kinase activity
AU - Miranda, Claudia
AU - Zanotti, Giuseppe
AU - Pagliardini, Sonia
AU - Ponzetto, Carola
AU - Pierotti, Marco A.
AU - Greco, Angela
PY - 2002/11/28
Y1 - 2002/11/28
N2 - Activation of tyrosine kinase receptors is associated with human tumors. Tumorigenic versions of several RTKs, such as Ret, Kit and Met carry activating mutations at highly conserved residues of the tyrosine kinase domain. We have investigated the effect of some of these mutations on the NTRK1/NGF receptor, for which no naturally occurring activating point mutations have been so far detected. We introduced the following mutations in NTRK1 tyrosine kinase domain: (i) D668N equivalent to Met D1246N associated to HPRC; (ii) D668V modelled on Kit D816V found in mastocytosis; (iii) M688T corresponding to Ret M918T associated to the cancer syndrome MEN2B. The Met-like mutation rendered the NTRK1 receptor more responsive to ligand, as observed for the corresponding mutation in Met. On the contrary the Kit-like D668V resulted as neutral mutation. Surprisingly, the MEN2B-like M688T completely abrogated NTRK1 receptor activity, resulting as a loss of function mutation. Our results show that the mutations tested, although involving conserved amino acids in highly homologous regions, exert distinct effects in different receptors, and suggest a very peculiar auto-inhibitory mechanism for NTRK1.
AB - Activation of tyrosine kinase receptors is associated with human tumors. Tumorigenic versions of several RTKs, such as Ret, Kit and Met carry activating mutations at highly conserved residues of the tyrosine kinase domain. We have investigated the effect of some of these mutations on the NTRK1/NGF receptor, for which no naturally occurring activating point mutations have been so far detected. We introduced the following mutations in NTRK1 tyrosine kinase domain: (i) D668N equivalent to Met D1246N associated to HPRC; (ii) D668V modelled on Kit D816V found in mastocytosis; (iii) M688T corresponding to Ret M918T associated to the cancer syndrome MEN2B. The Met-like mutation rendered the NTRK1 receptor more responsive to ligand, as observed for the corresponding mutation in Met. On the contrary the Kit-like D668V resulted as neutral mutation. Surprisingly, the MEN2B-like M688T completely abrogated NTRK1 receptor activity, resulting as a loss of function mutation. Our results show that the mutations tested, although involving conserved amino acids in highly homologous regions, exert distinct effects in different receptors, and suggest a very peculiar auto-inhibitory mechanism for NTRK1.
KW - NTRK1
KW - Oncogenic activation
KW - Tyrosine kinase receptors
UR - http://www.scopus.com/inward/record.url?scp=18744382121&partnerID=8YFLogxK
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U2 - 10.1038/sj.onc.1206052
DO - 10.1038/sj.onc.1206052
M3 - Article
C2 - 12447696
AN - SCOPUS:18744382121
VL - 21
SP - 8334
EP - 8339
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 54
ER -