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Cell Signalling and Gene Expression Mediated by RET

Cell Signalling and Gene Expression Mediated by RET

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Published by ifti007
Germline mutations of the RET proto-oncogene cause
multiple endocrine neoplasia (MEN) 2A or 2B by
different mechanisms. As is the case for other receptor
tyrosine kinases, mutant RET recruits a variety of
signalling molecules via phosphorylated tyrosine
residues present in the kinase domain and carboxyterminal
tail. As we previously reported, the signaling
via phosphorylated tyrosine 1062 plays a crucial role
in the transforming activities of both RET-MEN2A
and RET-MEN2B mutant protein. Interestingly, this
single tyrosine residue represents a binding site for
several signalling molecules including SHC, Enigma,
SNT/FRS2, DOK and IRS1 and is responsible for activation
of the RAS/ERK, PI3-K/AKT, JNK,
p38MAPK and ERK5 signalling pathways. Amongst
these, the PI3-K/AKT and JNK pathways appeared to
be more strongly activated in the cells expressing
RET-MEN2B than in the cells expressing RETMEN2A,
suggesting the possibility that these pathways
may be involved in the disease phenotype. In
addition, RET is alternatively spliced to produce three
isoforms and the splicing site is present just downstream
of tyrosine 1062. These isoforms play different
roles for the tumour development associated with
MEN 2 or the development of the kidney and the
enteric nervous system. Moreover, using differential
display analysis, we identified several genes whose
expression is highly induced by RET-MEN2B mutant
proteins. The differential gene expression by RETMEN2A
and RET-MEN2B may also be important for
the development of their phenotypes.
Germline mutations of the RET proto-oncogene cause
multiple endocrine neoplasia (MEN) 2A or 2B by
different mechanisms. As is the case for other receptor
tyrosine kinases, mutant RET recruits a variety of
signalling molecules via phosphorylated tyrosine
residues present in the kinase domain and carboxyterminal
tail. As we previously reported, the signaling
via phosphorylated tyrosine 1062 plays a crucial role
in the transforming activities of both RET-MEN2A
and RET-MEN2B mutant protein. Interestingly, this
single tyrosine residue represents a binding site for
several signalling molecules including SHC, Enigma,
SNT/FRS2, DOK and IRS1 and is responsible for activation
of the RAS/ERK, PI3-K/AKT, JNK,
p38MAPK and ERK5 signalling pathways. Amongst
these, the PI3-K/AKT and JNK pathways appeared to
be more strongly activated in the cells expressing
RET-MEN2B than in the cells expressing RETMEN2A,
suggesting the possibility that these pathways
may be involved in the disease phenotype. In
addition, RET is alternatively spliced to produce three
isoforms and the splicing site is present just downstream
of tyrosine 1062. These isoforms play different
roles for the tumour development associated with
MEN 2 or the development of the kidney and the
enteric nervous system. Moreover, using differential
display analysis, we identified several genes whose
expression is highly induced by RET-MEN2B mutant
proteins. The differential gene expression by RETMEN2A
and RET-MEN2B may also be important for
the development of their phenotypes.

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Categories:Types, Research
Published by: ifti007 on Feb 09, 2013
Copyright:Attribution Non-commercial

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02/09/2013

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