TY - JOUR
T1 - Chapter 4 c-Abl and Insulin Receptor Signalling
AU - Genua, Marco
AU - Pandini, Giuseppe
AU - Cassarino, Maria Francesca
AU - Messina, Rosa Linda
AU - Frasca, Francesco
PY - 2009
Y1 - 2009
N2 - Insulin Receptor (IR) and IGF-I receptor (IGF-IR) are homolog but display distinct functions: IR is mainly metabolic, while IGF-IR is mitogenic. However, in some conditions like foetal growth, cancer and diabetes, IR may display some non-metabolic effects like proliferation and migration. The molecular mechanisms underlying this 'functional switch of IR' have been attributed to several factors including overexpression of ligands and receptors, predominant IR isoform expression, preferential recruitment of intracellular substrates. Here, we report that c-Abl, a cytoplasmic tyrosine kinase regulating several signal transduction pathways, is involved in this functional switch of IR. Indeed, c-Abl tyrosine kinase is involved in IR signalling as it shares with IR some substrates like Tub and SORBS1 and is activated upon insulin stimulation. Inhibition of c-Abl tyrosine kinase by STI571 attenuates the effect of insulin on Akt/GSK-3β phosphorylation and glycogen synthesis, and at the same time, it enhances the effect of insulin on ERK activation, cell proliferation and migration. This effect of STI571 is specific to c-Abl inhibition, because it does not occur in Abl-null cells and is restored in c-Abl-reconstituted cells. Numerous evidences suggest that focal adhesion kinase (FAK) is involved in mediating this c-Abl effect. First, c-Abl tyrosine kinase activation is concomitant with FAK dephosphorylation in response to insulin, whereas c-Abl inhibition is accompanied by FAK phosphorylation in response to insulin, a response similar to that observed with IGF-I. Second, the c-Abl effects on insulin signalling are not observed in cells devoid of FAK (FAK-/- cells). Taken together these results suggest that c-Abl activation by insulin, via a modification of FAK response, may play an important role in directing mitogenic versus metabolic insulin receptor signalling.
AB - Insulin Receptor (IR) and IGF-I receptor (IGF-IR) are homolog but display distinct functions: IR is mainly metabolic, while IGF-IR is mitogenic. However, in some conditions like foetal growth, cancer and diabetes, IR may display some non-metabolic effects like proliferation and migration. The molecular mechanisms underlying this 'functional switch of IR' have been attributed to several factors including overexpression of ligands and receptors, predominant IR isoform expression, preferential recruitment of intracellular substrates. Here, we report that c-Abl, a cytoplasmic tyrosine kinase regulating several signal transduction pathways, is involved in this functional switch of IR. Indeed, c-Abl tyrosine kinase is involved in IR signalling as it shares with IR some substrates like Tub and SORBS1 and is activated upon insulin stimulation. Inhibition of c-Abl tyrosine kinase by STI571 attenuates the effect of insulin on Akt/GSK-3β phosphorylation and glycogen synthesis, and at the same time, it enhances the effect of insulin on ERK activation, cell proliferation and migration. This effect of STI571 is specific to c-Abl inhibition, because it does not occur in Abl-null cells and is restored in c-Abl-reconstituted cells. Numerous evidences suggest that focal adhesion kinase (FAK) is involved in mediating this c-Abl effect. First, c-Abl tyrosine kinase activation is concomitant with FAK dephosphorylation in response to insulin, whereas c-Abl inhibition is accompanied by FAK phosphorylation in response to insulin, a response similar to that observed with IGF-I. Second, the c-Abl effects on insulin signalling are not observed in cells devoid of FAK (FAK-/- cells). Taken together these results suggest that c-Abl activation by insulin, via a modification of FAK response, may play an important role in directing mitogenic versus metabolic insulin receptor signalling.
KW - Abl tyrosine kinase
KW - Focal adhesion kinase
KW - IGF-I receptor
KW - Insulin receptor
KW - Metabolic effect
KW - Mitogenic effect
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UR - http://www.scopus.com/inward/citedby.url?scp=61349183296&partnerID=8YFLogxK
U2 - 10.1016/S0083-6729(08)00604-3
DO - 10.1016/S0083-6729(08)00604-3
M3 - Article
C2 - 19251035
AN - SCOPUS:61349183296
VL - 80
SP - 77
EP - 105
JO - Vitamins and Hormones
JF - Vitamins and Hormones
SN - 0083-6729
IS - C
ER -