FUNCTIONAL DOMAINS OF THE INSULIN-RECEPTOR RESPONSIBLE FOR CHEMOTACTIC SIGNALING

The insulin receptor mediates a variety of cellular responses to insul in, including glucose transport, endocytosis, and cell proliferation. The role of the insulin receptor in mediating cellular motility has no t, however, been extensively investigated. In this report, we demonstr ate that chinese hamster ovary (CHO) cells that normally have low conc entrations of insulin receptor display chemotaxis toward insulin after overexpression of the wild type human insulin receptor. Chemotaxis to ward insulin proceeded through a pertussis toxin-sensitive pathway and required both tyrosine kinase activity and tyrosine autophosphorylati on of the regulatory region of the beta-subunit. In contrast, the auto phosphorylation sites in the carboxyl terminus of the receptor were no t required for chemotactic activity. A mutation in the juxtamembrane r egion, which disabled tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1), also prevented the chemotactic response, suggest ing a possible role for IRS-1 in chemotactic signaling. In the absence of insulin receptor, however, the presence of excess transfected IRS- 1 was not sufficient to mediate chemotaxis toward insulin. These resul ts demonstrate that the intact insulin receptor can stimulate a chemot actic signaling pathway and that this initial pathway more closely cor relates with that for insulin-stimulated cell proliferation than for i nsulin-stimulated receptor endocytosis.