Deletion of exon 21 of the insulin receptor eliminates tyrosine kinase activity but preserves mitogenic signaling.

Abstract:

:To study the function of exon 21 of the insulin receptor, a mutant human insulin receptor lacking this domain was constructed. The mutant HIR delta E21 cDNA was transfected into Rat-1 fibroblasts and stable cell lines were selected. The HIR delta E21 receptors were expressed on the cell surface, and they bound insulin with the same affinity as did the wild-type-expressing cell line, hIRcB. The HIR delta E21 receptors did not display detectable autophosphorylation or kinase activity, and as expected, internalization was impaired and metabolic signaling properties were absent. Unexpectedly, insulin's ability to stimulate DNA synthesis in cells expressing HIR delta E21 receptors was far greater than that in the parental Rat-1 cells and equal to that measured in the hIRcB cell line. The enhanced mitogenic signaling properties of the HIR delta E21 receptors was confirmed by showing that treatment of HIR delta E21 cells with a human-specific insulin-mimetic anti-insulin receptor antibody also led to enhanced DNA synthesis. Thus, although no insulin receptor autophosphorylation or kinase activity was detectable in HIR delta E21 cells, these cells displayed enhanced insulin-induced mitogenic signaling. These results suggest that an alternative non-kinase-dependent stimulus-response pathway exists for the long-term biological effects of insulin.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Rolband GC,Williams JF,Webster NJ,Hsu D,Olefsky JM

doi

10.1021/bi00212a021

subject

Has Abstract

pub_date

1993-12-14 00:00:00

pages

13545-50

issue

49

eissn

0006-2960

issn

1520-4995

journal_volume

32

pub_type

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