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Studying the Hypothalamic Insulin Signal to Peripheral Glucose Intolerance with a Continuous Drug Infusion System into the Mouse Brain
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Role of c-Abl in directing metabolic versus mitogenic effects in insulin receptor signaling

Francesco Frasca1, Giuseppe Pandini, Roberta Malaguarnera

  • 1Endocrinologia, Dipartimento di Medicina Interna e di Medicina Specialistica, Università di Catania, Ospedale Garibaldi, Nesima, 95122 Catania, Italy. f.frasca@unict.it

The Journal of Biological Chemistry
|July 11, 2007
PubMed

Insights

The cytoplasmic tyrosine kinase, c-Abl, plays a key role in insulin signaling by influencing focal adhesion kinase (FAK) activity. Inhibiting c-Abl kinase activity alters insulin

Area of Science:

  • Cellular signaling
  • Biochemistry
  • Molecular biology

Background:

  • c-Abl is a cytoplasmic tyrosine kinase.
  • c-Abl participates in various signal transduction pathways.
  • Its role in insulin receptor signaling was previously unclear.

Purpose of the Study:

  • To investigate the involvement of c-Abl in insulin receptor signaling.
  • To elucidate the downstream effects of c-Abl activation or inhibition in response to insulin.
  • To determine the role of focal adhesion kinase (FAK) in mediating c-Abl's effects on insulin signaling.

Main Methods:

  • Utilized STI571 to inhibit c-Abl tyrosine kinase activity.
  • Examined insulin-stimulated phosphorylation of Akt/GSK-3beta and ERK.
  • Assessed glycogen synthesis, cell proliferation, and migration.
  • Employed Abl-null and c-Abl-reconstituted cells to confirm specificity.
  • Investigated FAK phosphorylation status and utilized FAK(-/-) cells.

Main Results:

  • Insulin stimulation activates c-Abl tyrosine kinase.
  • c-Abl inhibition by STI571 attenuates insulin's effects on Akt/GSK-3beta phosphorylation and glycogen synthesis.
  • c-Abl inhibition enhances insulin's effects on ERK activation, cell proliferation, and migration.
  • These effects are specific to c-Abl and mediated through FAK.
  • Insulin stimulation leads to c-Abl activation and FAK dephosphorylation, while c-Abl inhibition results in FAK phosphorylation.

Conclusions:

  • Insulin receptor signaling involves c-Abl activation.
  • c-Abl modulates FAK response to insulin.
  • c-Abl plays a critical role in directing the balance between mitogenic and metabolic insulin signaling pathways.

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