INVESTIGADORES
COLUCCIO LESKOW Federico
artículos
Título:
Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B
Autor/es:
JIMENA GIUDICE; FEDERICO COLUCCIO LESKOW; DONNA J ARNDT-JOVIN; THOMAS M JOVIN; ELIZABETH A JARES-ERIJMAN
Revista:
JOURNAL OF CELL SCIENCE
Editorial:
COMPANY OF BIOLOGISTS LTD
Referencias:
Lugar: London; Año: 2011 vol. 1 p. 801 - 811
ISSN:
0021-9533
Resumen:
Insulin signaling comprises a complex cascade of events, playing a key
role in the regulation of glucose metabolism and cellular growth.
Impaired response to insulin is the hallmark of diabetes, whereas
upregulated insulin activity occurs in many cancers. Two splice variants
of the insulin receptor (IR) exist in mammals: IR-A, lacking exon 11,
and full-length IR-B. Although considerable biochemical data exist on
insulin binding and downstream signaling, little is known about the
dynamics of the IR itself. We created functional IR transgenes fused
with visible fluorescent proteins for use in combination with
biotinamido-caproyl insulin and streptavidin quantum dots. Using
confocal and structured illumination microscopy, we visualized the
endocytosis of both isoforms in living and fixed cells and demonstrated a
higher rate of endocytosis of IR-A than IR-B. These differences
correlated with higher and sustained activation of IR-A in response to
insulin and with distinctive ERK1/2 activation profiles and gene
transcription regulation. In addition, cells expressing IR-B showed
higher AKT phosphorylation after insulin stimulation than cells
expressing IR-A. Taken together, these results suggest that IR signaling
is dependent on localization; internalized IRs regulate mitogenic
activity, whereas metabolic balance signaling occurs at the cell
membrane.
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